A Concise Synthesis of rac-Ambrox via the Palladium(0)-Catalyzed Carboalkoxylation of an Allylic Ammonium Salt, as Compared to a Formaldehyde Hetero Diels–Alder Approach

Article abstract of DOI:10.1002/hlca.201900097

Acidic cyclization of either the diethylallylamines 29b or 30, followed by a 1.5 mol-% Pd-catalyzed carbomethoxylation of quaternized 31b, leads to the methyl ester 36a. This latter could also be obtained in optically pure form by carbomethoxylation of the corresponding (+)-acetate. Final reduction-cyclization may be conducted as earlier described, towards the desired odoriferous rac-Ambrox 38a, or its pure (?)-enantiomer. Generation of a π-allyl Pd complex from an allylic ammonium salt, followed by carboalkoxylation is novel. In only five chemical steps starting from farnesene 2, the present work constitutes the most concise total synthesis of rac-Ambrox 38a to date.

Full text of DOI:10.1002/hlca.201900097

HELVETICA
chimica acta
Accepted Article
Title: A Concise Synthesis of rac-Ambrox® via the Pd° Catalyzed
Carboalkoxylation of an Allylic Ammonium Salt, as Compared to
a Formaldehyde Hetero Diels-Alder Approach
Authors: Christian Chapuis, David Skuy, and Claude-Alain Richard
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10.1002/hlca.201900097
Helvetica Chimica Acta
1
A Concise Synthesis of rac-Ambrox® via the Pd0 Catalyzed Carboalkoxylation
of an Allylic Ammonium Salt, as Compared to a Formaldehyde Hetero Diels-
Alder Approach
Christian Chapuis*, David Skuy, and Claude-Alain Richard
Dedicated to Dr. V. Rautenstrauch on the occasion of his 82th birthday
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Acidic cyclisation of either the diethylallylamines 29b or 30, followed by a 1.5 mol-% Pd-
catalyzed carbomethoxylation of quaternized 31b, leads to the methyl ester 36a. This latter could
also be obtained in optically pure form by carbomethoxylation of the corresponding (+)-acetate.
Final reduction-cyclisation may be conducted as earlier described, towards the desired
odoriferous rac-Ambrox® 38a, or its pure (-)-enantiomer. Generation of a -allyl Pd complex
from an allylic ammonium salt, followed by carboalkoxylation is novel. In only five chemical
steps starting from farnesene 2, the present work constitutes the most concise total synthesis of
rac-Ambrox® 38a to date.
Keywords: Palladium, carbomethoxylation, allylic, ammonium, Ambrox®
______________________________________________________________________________
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Introduction: -The simple conditions previously reported by Margot and Schlosser for the
“formal” hetero Diels-Alder reaction between paraformaldehyde and myrcene 1 [1-4],
encouraged us to extend this reaction to other dienes. In particular, to the now readily available
farnesene 2 [5-8] (Scheme 1), -pyronene 31) [9-18] (Scheme 2), the known bicyclic diene 42)
[22-32], and 2,3-dimethylidenenorbornane 53) [35-39]; as well as to the unreported diene 6
(Scheme 3). Our simple basic concept consisted of cleaving the resulting dihydropyran allylic C-
O bond via a Birch reduction [3][40], followed by cyclization of the corresponding homoallylic
alcohol under acidic conditions [41-45], in order to create new tetrahydrofuran derivatives,
which might possess amber-like scents [46]. We also wanted to apply unreported
carboalkoxylation conditions to achieve a short synthesis of rac-Ambrox®.
Results and discussion. – The known tetrahydropyran 74) [1-4] was obtained in 64% crude yield
from 1 (paraformaldehyde, AcOH, 130°C). A simple distillation allowed the isolation of >96%
.
pure material in 18% yield. Further catalytic cyclization (0.1 mol.-equiv. BF3 OEt2, CH2Cl2,
20°C) afforded the bicyclic ether 8 in 47% yield. Then Birch cleavage under simple conditions
(Li, H2NCH2CH2NH2, 20°C, 69% yield) furnished the primary homoallylic alcohol 9, which was
subsequently, quantitatively, cyclized to give a 87:13 mixture of tetrahydrofuran derivatives
trans-/cis-10 (MeSO3H, CH2Cl2, 20°C).
HERE SCHEME 1
1
)
)
)
See the Supplementary Material for analytical data.
2
3
For the (+)-enantiomer, see [19-21].
This “formal” HDA-cycloaddition may also be seen either as a neutral Prins, or concerted ene-type reaction
followed by acidic cyclisation, although this alternative stepwise mechanism is not applicable to dienes
such as 5. Alternatively, acidic protonation of formaldehyde reacting with the diene by forming a tertiary
allylic cation could lead, after cyclization, towards the observed skeletons. For a diastereoselective
example of such a “formal” HDA-reaction, see [33], for alternative catalytic conditions, see [34].
This compound exhibits a lemon, rosy, citronellol, geraniol and citral scent, as well as the following 13C-
NMR analytical data: 135.6 (s); 131.7 (s); 124.0 (d); 119.6 (d); 65.6 (t); 64.4 (t); 37.1 (t); 28.6 (t); 25.9 (t);
25.7 (q); 17.7 (q). Bp: 94°C/0.7 mbar.
4
)
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Similarly, the homologous farnesene 2 was subjected to the same sequence to afford the
corresponding pure dihydropyran 11 in 15% isolated yield,5) while cyclization allowed us to
isolate traces of isomerized -12, as well aspure -12 (14% yield). When this latter was
submitted to hydrogenation conditions (5% Pd/C, AcOEt, 88% yield), a 77:23 mixture of
trans/cis stereoisomers 13 was obtained. This stereochemistry may eventually result from the
faster hydrogenation of -12, a less stable, but more accessible, trisubstituted double bond when
compared to -12, thus driving the equilibrium towards the double bond isomerization.6) Birch
reduction of -12, led to the homoallylic alcohol 14 (59% yield), which was finally cyclized to
the Ambrox® constitutional isomers 15 (MeSO3H, CH2Cl2, 51% yield, 55:45 mixture of
stereoisomers). Neither derivatives 12, 13 nor 15 exhibited a strong amber-like scent, although
all of them were weakly olfactorily active, despite analytical evidence for the absence of
regioisomers. Since the reversed regioselectivity would have been synthetically more interesting
during the cycloaddition, we decided to invert the sequence by studying the hetero Diels-Alder
reaction of the cyclic dienes. Thus, when -pyronene 3 was used, the [4+2] cycloaddition
afforded a 9:1 mixture of regioisomers 8 and 167) in 66% crude yield. Regioisomer 8 could be
isolated pure in 38% yield by CC/SiO2, while Birch reduction of a 8:2 mixture of 8/168) gave the
reported minor homo-allylic alcohol 18 [48-50], which was subsequently cyclized to afford the
bicyclic ether 19 [51-52] in 69% yield as a 83:17 trans/cis mixture.9)
HERE SCHEME 2
5
)
)
When 2 was treated with paraformaldehyde and 0.05 mol-equiv. of SnCl4 in CH2Cl2 at 20°C, we isolated
the Prins by-product in 7% yield. For analytical data of (E)-5-methyl-9-methylene-2-(prop-1-en-2-
yl)undeca-5,10-dien-1-ol, see the Supplementary Material.
6
Ground state energy (B3LYP-6-31G**): -12: 0.00 kcal/mol; -12: 1.29 kcal/mol; (6aRS,10aRS,10bSR)-
7,7,10a-trimethyl-3,4,6,6a,7,8,9,10,10a,10b-decahydro-1H-benzo[h]isochromene:
1.90
kcal/mol;
(6aRS,10aRS,10bRS)-7,7,10a-trimethyl-3,5,6,6a,7,8,9,10,10a,10b-decahydro-1H-benzo[h]isochromene:
1.79 kcal/mol [47].
7
8
9
)
)
)
J. Coulomb (Firmenich SA, unpublished results, 2010) obtained a 3:1 mixture of 8/16 in 39% yield by using
.
0.1 mol.-equiv. of BF3 OEt2 in CH2Cl2 at 20°C for 4 h.
Under modified Birch conditions (Li, MeNH2, THF, -78°C, [3]) the reduction of 8/16 additionally afforded
traces of the side product 17, isolated in 10% yield, as a result of a double bond isomerization.
C. Fehr (Firmenich SA, unpublished results, 2008) isolated 19 in 78% yield as a 88:12 trans/cis mixture by
using 0.6 mol.-equiv of FeCl3, 50 mg/mmol SiO2 60Å, in CH2Cl2/ClCH2CH2Cl, after 3.5 h at 20°C [53].
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The analogous cycloaddition performed on diene 4 afforded again, essentially, the undesired
regioisomer -12 in 25% isolated yield. We also applied these hetero Diels-Alder conditions to
diene 5 (22% isolated yield), since the Birch reduction of dihydropyran 20 led to the homo-
allylic alcohol 21 (Li, H2NCH2CH2NH2, 20°C, 41% yield),10) earlier used as optically active
intermediate in a synthesis of (-)-(Z)--santalol [54]. Further direct intramolecular acidic
cyclization gave the five-membered ring ether 22 in 48% yield, as a 79:21 endo/exo mixture. For
the sake of completeness, we also wanted to perform this hetero cycloaddition on the unreported
diene 6 (Scheme 3). We initially decided to synthetize it by applying the Wittig methodology
described by Vig et al. [55-56]. Thus a haloform reaction on the commercially available dihydro-
-ionone 23a afforded the reported acid 23b [57-61], which was quantitatively transformed into
the corresponding known acid chloride 23c [9]. Alternatively, reduction of acid 23b (Scheme 3)
to the known primary alcohol 24a11) [19][57][60], allowed us, after re-oxidation to the reported
aldehyde 23d [9][62] (PCC, CH2Cl2, 66% yield)12) to perform either a vinyl Grignard addition
.
leading to the allylic alcohol 24b (vinylMgBr, 0.2 mol.-equiv. LaCl3 2LiCl, THF, 0°C [63]),
isolated in 42% yield besides 24a, or a more efficient ethynyl Grignard addition towards the
analogue 24c (HCCMgBr, Et2O, 94% yield). Treatment of this latter secondary propargylic
alcohol 24c with LiAlH4 also generated 24b in 49% yield.13) With two potential precursors in
hand, we first treated the acid chloride 23c in the presence of Li2MnCl4 with vinylMgBr (14%
yield), and co-isolated in 6% yield the known by-product 25, resulting from a concurrent
intramolecular Friedel-Craft reaction [9].14) The desired intermediate enone 23e was more
10
)
)
This alcohol, possessing paper, woody, straw, and sawdust organoleptic facets, exhibits the following
complementary analytical data: IR: 3325, 2951, 2866, 1444, 1378, 1276, 1115, 1039, 1021, 986, 870. MS:
152 (20, M+.), 124 (29), 93 (100), 91 (32), 80 (26), 77 (20).
11
This alcohol exhibits the following complementary 13C-NMR analytical data: 136.9 (s); 127.1 (s); 63.6 (t);
39.9 (t); 35.0 (s); 33.6 (t); 32.8 (t); 28.6 (2q); 24.9 (t); 19.8 (q); 19.6 (t). Dusty, metallic, weak odor.
Incidentally, oxidation of aldehyde 23d under Jones conditions afforded acid 23b in 81% yield.
With 32% isolated yield (CC/SiO2+1%/w AgNO3), Lindlar hydrogenation of 24c in cyclohexane was less
efficient.
12
13
)
)
14
)
This compound with the following 13C-NMR analytical data: 222.6 (s); 156.1 (s); 114.7 (d); 51.3 (s); 41.1
(t); 40.6 (t); 34.9 (s); 33.2 (t); 29.8 (q); 26.8 (q); 23.2 (q); 18.5 (t), exhibits a beetroot, earthy, pine and
incense scent. We also isolated (1RS,5RS)-6,6-dimethyl-9-methylenebicyclo[3.3.1]nonan-2-one in 3% yield
(see Supplementary Material). This compound, first delivered to our perfumers by B. Winter (Firmenich
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cleanly obtained by oxidation (MnO2, CH2Cl2, 34% yield) of the vinylic carbinol 24b.15) The
+
final Wittig reaction (Ph3PCH3 Br-, NaH, DMSO, THF) unfortunately afforded diene 6 in a poor
15% yield. Alternatively, treatment of farnesene 2 with commercially available DABSO16) in the
.
presence of BF3 OEt2 in MeCN at 50°C [66], afforded a 2:1 mixture of sulfolenes 26/27 in 36%
.
crude yield (13 and 2% isolated yield, respectively). Cyclization of pure 26 with BF3 OEt2 in
MeCN at 0°C afforded, after 80% partial conversion, pure 27. Under the same conditions, a
crude 2:1 mixture of 26/27 also afforded in 66% yield a 2:1 mixture of 27/28. Alternatively,
.
cyclisation of pure 26 with BF3 OEt2 and AcOH in CH2Cl2 at 30°C gave essentially 28 in 47%
yield [67]. An alternative sequence was explored by treating the known vinyl carbinol 24d [68-
69] with DABSO in the presence of MsCl [66], but, as underlined in the original report, the use
of a DMAP.SO2 complex should be more efficient to afford directly sulfolene 27, since our
conversion was very poor. The thermal treatment of 27 at 160°C in pyridine then afforded the
desired diene 6 in 57% yield, while that of 28 afforded diene 4 in 68% yield [70].17)
HERE SCHEME 3
Since this approach was not much more attractive than the Wittig methodology, we envisaged
another strategy starting from the known precursors 29a,b [72-78]. Thus, cyclisation of 29b
.
using an excess of BF3 OEt2 and AcOH in CH2Cl2 at 30°C afforded quantitatively a 26:58:16
mixture of 30/31g/31a from which pure 31g was isolated in 33% yield after chromatography,18)
SA, unpublished results, 2006), exhibits the following olfactory properties: aromatic, beeswax, honey,
camphoraceous, woody, Kephalis.
15
)
)
Similar oxidation of 24c afforded 23f in 41% yield.
16
1,4-Diazabicyclo[2.2.2]octane bis (sulfur dioxide) adduct. The MS analyses of 26 and 27 are reminiscent to
that of 2, and 6, due to the easy chelotropic elimination of SO2, respectively [64-65]. This instability, with
respect to the reaction temperature conditions, is in all cases detrimental to the isolated yields. Treatment of
5 with either DABSO, or Riecke Mg failed [64-65].
17
)
)
Alternative treatment of 27 with NaHCO3 in EtOH at 120°C in analogy to [71] gave ca. only 30%
conversion after 18h. Alternatively, treatment of 27 with AcOH and (CH2O)n at 130°C failed to afford
directly the desired heterocycloadduct. Under these conditions, myrcenol [55], with the following
complementary 13C-NMR analytical data: 146.2 (s); 138.9 (d); 115.7 (t); 113.2 (t); 70.8 (s); 43.7 (t); 31.7
(t); 29.2 (2q); 22.9 (t), afforded the corresponding cycloadduct in 13% yield (see Supplementary Material).
The 13C-NMR analysis of the crude material showed no traces of the -isomer 31b.
18
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while an excess of conc. H2SO4 in CH2Cl2 at 30°C furnished in quantitative yield a 74:26
mixture of 31b/31r.19) Both rearranged and tetrasubstituted olefins, separable by
chromatography, were isolated in 7% and 39% yield, respectively. The monocyclization could be
selectively obtained by using MeSO3H in CH2Cl2 at 0°C, thus affording in 60% yield a 78:22
mixture of E/Z-30 after distillation. The best Brønsted acid conditions were observed with an
excess of CF3SO3H in MeNO2 at -20° to 0°C, affording in 81% yield either a 7:3 mixture of
31a/31g when the reaction was immediately quenched at -20°C, or 31b20) in 75% yield when the
reaction was quenched at 0°C before the formation of 31r. Pure homoallylic amine 31g was
treated with 60% aq. H2O2 in EtOH, to afford pure diene 4 in 58% yield after distillation.21)
HERE SCHEME 4
The carbonylation of allylic amines in the presence of either a Pd-phosphine or a dicobalt
octacarbonyl complex to afford -unsaturated amides has been reported [79-80]22), and
Rautenstrauch et al. earlier observed that quaternisation of the commercially available
geranyldiethylamine 29a with either H+ or EtI in EtOH at 60°C [86-87], followed by in situ
19
)
Theoretical B3LYP-6-31G** calculations suggest the following ground state energies: (1RS,2SR,4aRS)-31r
0.00 kcal/mol; (1RS,2RS,4aSR)-31r 0.38 kcal/mol; (1RS,2SR,4aSR)-31r 0.93 kcal/mol; (1RS,2RS,4aRS)-31r
1.42 kcal/mol [47]. The isolated stereoisomer does not correspond to the thermodynamically more stable
one. Its stereochemistry was confirmed by NOE evidences between the pseudo axial secondary Me and the
axial Me of the gem-diMe moiety, as well as between the pseudo axial CH2-N and the quaternary Me of the
ring junction. Treatment of 30 with either 30% H2O2/EtOH, or MCPBA/CH2Cl2 failed to afford 6 after
distillation. The Wittig preparations of 6 (vide supra) nevertheless allowed, for analytical purposes, to
obtain both cycloadduct 32 (AcOH, (CH2O)n, 130°C, 57% yield), and its Birch reduced corresponding
homoallylic alcohol 33 (35% yield, Scheme 4).
20
21
)
)
When 29f was similarly cyclized with either CF3SO3H, or H2SO4 at 0° to 20°C, the pyrolidine derived
analogue of 31b was isolated in 46% yield (see Supplementary Material).
When a 55:45 mixture of 31g/31a was treated with 60% aq. H2O2 in EtOH, both pure 4 and 31a were
isolated by CC/SiO2 in 25% and 27% yield, respectively. The corresponding N-oxides could not be put in
evidence.
22
)
For 2-((4aS,8aS)-2,5,5,8a-tetramethyl-3,4,4a,5,6,7,8,8a-octahydronaphthalen-1-yl)acetamide, see [77]. For
Ni-catalyzed carboxylation of benzylic ammonium derivatives using CO2, see [81]. For a review on this
subject, see [82]. For carbomethoxylation of benzylic amines using Pd2(dba)3, see [83-84]. For Ni-catalyzed
C-P coupling of benzyl and allyl ammonium salts with R2P(O)H derivatives, see [85].
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carboethoxylation (0.01 mol.-equiv. Pd(PPh3)4, CO, 60 bar, EtOH, 60°C, 72h) enable a clean
one-C atom homologation to afford the known ethyl ester 34a in 73% yield as a 85:15 E/Z
mixture [88-90]23). The EtOH may eventually be substituted by MeOH, since both the kinetic
and conversion are increased in this later case. Quaternization may also be performed from the
commercially available primary allylic amine 29c with either three mol.-equiv. of MeI, or by
simple protonation with one mol.-equiv. of 96% H2SO4 in MeOH/THF to afford in 24-25% yield
34c as a 84:16 to 80:20 mixture of E/Z stereoisomers after 48h at 60°C under 60 bars of CO
[91]24). In our hands, farnesyldiethylamine 29b likewise afforded the ethyl ester 34b in 15%
yield as a 76:24 E/Z mixture (EtI, EtOH, 60°C, 60 bar CO, 0.01 mol.-equiv. Pd(PPh3)4) [92]. The
chemical yield increased to 32% when a 1:1 mixture of EtOH/THF was used.25) Similarly, the
monocyclofarnesyldiethylamine 30 also furnished the known ethyl ester 35b in 52% yield as a
65:35 E/Z mixture (EtI, 0.01 mol.-equiv. Pd(PPh3)4, CO, 60 bar, EtOH, 60°C, 87h) [98-99]26). In
order to avoid E/Z-mixtures, we applied these unreported conditions to 31b (MeI, 0.015 mol.-
equiv. Pd(PPh3)4, MeOH/THF 1:1, CO, 60 bar, 60°C, 144h, 45% conversion, 31% yield), so that
the alkyl esters 36a,b [92][104-108]27) may further be reduced into ambrol 37 as described by
23
)
V. Rautenstrauch, J. Currie, and A. Charpilloz, (Firmenich SA, unpublished results 1991-1992). This ethyl
ester exhibits the following complementary MS analytical data: E-stereoisomer 210 (2, M+.), 167 (20), 122
(17), 109 (5), 107 (8), 96 (9), 93 (8), 81 (10), 69 (100), 41 (30). Z-stereoisomer 210 (3, M+.), 167 (14), 122
(23), 109 (13), 107 (16), 96 (9), 93 (7), 81 (12), 69 (100), 41 (33).
24
25
)
)
The Me ester 34c exhibits a rosy-like scent. Supplementary 13C-NMR analytical data of the Z-stereoisomer:
173.0 (s); 139.3 (s); 132.0 (s); 123.9 (d); 116.4 (d); 51.7 (q); 33.6 (t); 32.2 (t); 26.3 (t); 25.7 (q); 23.4 (q);
17.6 (q).
When the reaction temperature is superior to 75°C, Hofmann elimination becomes a competing side
reaction. The corresponding known Me esters 34d [93-97], (80:20 3E/3Z mixture, were more efficiently
obtained using 0.01 mol.-equiv of either Pd(PPh3)4, or PdBr2/(CH2PoPy2)2 (MeOH/THF, CO, 60 bar, 60°C,
22h, 52-55% yield, respectively, see Supplementary Material).
26
)
)
See the Supplementary Material for the corresponding known Me ester 35a [100-103]. The E-stereoisomer
possesses a bitter almond and tobacco-like scent in opposition to the weakly metallic character of the Z-
counterpart. See also the Supplementary Material for complementary analytical data of the corresponding
known acid 35c [93-97][100-103].
27
The reaction in pure and less nucleophilic EtOH was much more sluggish due to the poor solubility of 31b.
For comparison, complementary analytical data of the reported Me-ester -analogues [104-105] are
available in the Supplementary Material. Alternatively, (+)-36a was also obtained in 15-20% yield from
the reported corresponding (+)-((4aS,8aS)-2,5,5,8a-tetramethyl-3,4,4a,5,6,7,8,8a-octahydronaphthalen-1-
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Hagiwara et al. [114-115]28), prior to the final known cyclisation to rac-Ambrox® 38a [44-
45][53][77]. This regioselective carboalkoxylation methodology does not generate a
supplementary stereogenic center, as a critical point for the stereochemistry of the final product.
The known cyclization of N,N-diethyl geranylamine 29a towards -cyclogeranyldiethylamine 39
(40% aq. H2SO4, 120°C, 20h, 54%, [76]), followed by carbomethoxylation afforded the known
methyl -homocyclogeranate 40a (MeI, 0.015 mol.-equiv. Pd(PPh3)4, MeOH, THF, CO, 60°C,
60 bar, 47% conversion, 25% yield) [117-118]29). Finally, diene 5 was treated with Et2NH and
nBuLi in THF to afford the unreported diethyl amine 41 in 52% yield. When submitted to
carbomethoxylation conditions (MeI, 0.015 mol.-equiv. Pd(PPh3)4, MeOH, CO, 60 bars, 60°C,
yl)methyl acetate [109] ([]D20 = +117.8, c = 2.0, CHCl3; 0.01 mol.-equiv. Pd(PPh3)4, MeOH/THF 1:1, CO
60 bar, 70°C, 168h), in analogy to achiral former examples [88-91]. For KBr as additive, see [110]. The
essential
side
product
was
(-)-(4aS,8aS)-1,1,4a,6-tetramethyl-5-methylene-1,2,3,4,4a,5,8,8a-
octahydronaphthalene (21% yield) [45]. In situ isomerization of the homoallylic unsaturation of either
drimenylacetate [111-112], or 31a,g, under modified reaction conditions is actually under study. In a
20
comparative example, we also treated directly the (+)-bicyclofarnesol ([]D = +112.4, c = 2.2, CHCl3,
[30][45]) with 1.3 mol.-equiv. of KH complexed with 1.6 mol.-equiv. of 18-c-6-ether, and performed the
carbonylation (CO, 60 bar, 60°C, toluene, 72h, 40% conversion) under the conditions reported by
Rautenstrauch, [113] to afford the homologated acid (+)-36c in 2.8% yield after extractive hydrolysis [77].
For the hydrogenation of unsaturated esters into the corresponding unsaturated alcohols, see [116].
This material is characterized by a foul odor. For the ethyl ester 40b, see [119]. Under protonating
carboxylative conditions (96% H2SO4, THF, 0.01 mol.-equiv Pd(PPh3)4, 70% yield, Rautenstrauch, private
communication), the reported odorless -homocyclogeranic acid 40c was isolated with the following
complementary analytical data [119-121]: MS: 182 (22, M+.), 167 (70), 149 (8), 121 (22), 107 (100), 93
(13), 91 (15), 81 (11), 79 (13), 55 (9), 43 (10), 41 (15). When diethylgeranylamine 29a was cyclized with
CF3SO3H in MeNO2 at 0°C, pure - and -diethylcyclogeranylamines were isolated in 30% and 13% yield,
respectively. When -pyronene 3 was treated with lithium diethylamide, both 39 and its main regioisomer
were obtained as a 1:4 mixture in poor yield (see Exp. Part). It is thus preferable to use either cyclogeranyl
chloride, or -cyclocitral as starting material for amination. In analogy to the work of M. Beller et al. [122],
we also advantageously tested on 39 a commercially available ligand (0.01 mol.-equiv. PdBr2, 0.02 mol.-
equiv. P,P’-bis(ditBu phosphine)-o-xylene, MeI, CO, 60 bar, 60°C, MeOH, 2h, 31% yield). For a recent
and efficient generation of Pd0, see [123]. For in situ generation of CO, see [124].
28
29
)
)
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22% yield), we obtained the unreported methyl ester 42 as precursor of either 21, or (Z)--
santalol [54].30)
Conclusion. – The paraformaldehyde hetero Diels-Alder-like methodology applied to both diene
2, and 6, afforded the unsuitable regioisomers 11, and 32 for further transformations towards
rac-Ambrox® 38a, respectively. This regioselectivity could not be inverted by starting from the
cyclic dienes 4, as we also obtained the heterocyclic intermediate -12. After several
unsatisfactory alternative attempts, this obstacle was finally circumvented by using a more
efficient and regioselective methodology consisting of acidic cyclisation of either the
diethylallylamines 29b or 30, followed by a 1.5 mol-% Pd-catalyzed carbomethoxylation of
quaternized 31b, leading to the methyl ester 36a. This latter could also be obtained in optically
pure form by carbomethoxylation of the corresponding (+)-acetate. Final reduction-cyclisation
may be conducted as earlier described, towards the desired odoriferous rac-Ambrox® 38a, or its
pure (-)-enantiomer. Generation of a -allyl Pd complex from an allylic ammonium salt,
followed by carboalkoxylation according to the “in house” procedure of Rautenstrauch et al., is
novel31) [131]. With only five chemical steps from farnesene 2, the present report constitutes the
most concise total synthesis of rac-Ambrox® 38a, to date. In this latter case, sclareolide 38b may
be obtained in 73% yield according to the established lactonization procedure [77]27)32). This
methodology allows for both the separation and recuperation of either the desired ester, or the
non-converted starting material and/or unreactive homoallylic isomers, by a simple acidic
washing of the reaction mixture. In order to extend the scope of this carboalkoxylation using
Pd(II) coordinated to amphotere diphosphines as Pd0 precatalysts [122-123], we are now
exploring either the possibilities to start from pure, or mixtures of the corresponding -, or -
30
)
The corresponding acid and ethyl ester exhibit the following complementary analytical data: [54] MS: 166
(22, M+.), 138 (88), 93 (100), 91 (30), 79 (10), 77 (22); 194 (28, M+.), 166 (99), 121 (19), 93 (100), 92 (82),
91 (38), 79 (11), 77 (23), respectively. The latter exhibits a fruity, carob-bean, overripe fruit and estery
scent.
31
)
For allylic ammoniums as precursors of putative -allyl Pd complexes, see for example [125-127]. For
sterically less demanding leaving groups, we also similarly prepared the known characterized precursor 29d
[128-130], as well as the unreported analogs 29e and 29f. The regioisomer (2E,5E)-2-ethylidene-N,N,6,10-
tetramethylundeca-5,9-dien-1-amine as main side product of 29d was also isolated for analytical purpose
(see Supplementary Material).
32
)
For the quantitative LiAlH4 reduction of acid 36c to alcohol 37, see also [77].
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10.1002/hlca.201900097
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homoallylic amines/acetates, owing to the potential concomitant isomerization of the
unsaturation in either the presence of a supplementary additive, or by replacing MeOH/EtOH by
H3O+ in THF. Finally, we shall also study some examples of lactonization using bifunctional
hydroxy allyl amines.
Experimental Part
General, see [77]. The reactions with CO under pressure were performed by trained personnel, in
a specific secured high pressure laboratory cabin, equipped with detectors.
1,3,3-Trimethyl-2-(3-methylenepent-4-en-1-yl)cyclohex-1-ene 6. NaH (55% in min. oil, 137 mg,
3.13 mmol) was added to a soln. of Ph3PCH3Br (1306 mg, 3.66 mmol) in DMSO (5 ml). After
0.5 h at 20°C, then 0.5 h at 50°C, the reaction mixture was cooled to 20°C and a soln. of 23e
(220 mg, 1.045 mmol) in THF (5 ml) was added. After 18h at 20°C, the reaction mixture was
poured onto H2O and extracted with Et2O (3 x 10 ml). The org. phase was washed with H2O (2 x
10 ml), dried (Na2SO4) and concentrated in vacuo. Purification by CC/SiO2 (cyclohexane/AcOEt
99:1) afforded 6 in 15% yield. Alternatively, a soln. of 27 (12 mg, 0.045 mmol) in pyridine (3 ml
was heated at 150°C for 5 h. The cold reaction mixture was poured onto H2O, and extracted with
Et2O (3 x 10 ml). The org phase was washed with H2O (2 x 5 ml), dried (Na2SO4), concentrated,
then purified by CC/SiO2 (cyclohexane/AcOEt 99:1) to afford 6 in 57% yield. Rf = 0.92
1
(cyclohexane/AcOEt 95:5). IR: 2952, 2923, 2853, 1594, 1457, 1376, 1359, 989, 901, 890. H-
NMR: 6.40 (dd, J = 11.6, 18.0, 1H); 5.29 (d, J = 17.4, 1H); 5.07 (d, J = 10.3, 1H); 5.03 (d, J =
8.4, 2H); 2.27-2.23 (m, 2H); 2.18-2.15 (m, 2H); 1.93 (t, J = 6.4, 2H); 1.63 (s, 3H); 1.61-1.57 (m,
13
2H); 1.45-1.43 (m, 2H); 1.02 (s, 6H). C-NMR: 147.4 (s); 139.2 (d); 137.1 (s); 127.4 (s); 115.1
(t); 113.1 (t); 39.9 (t); 35.0 (s); 32.8 (t); 31.7 (t); 28.6 (2q); 27.8 (t); 20.0 (q); 19.6 (t). MS: 204
(13, M+.), 189 (30), 175 (10), 161 (14), 148 (16), 137 (32), 133 (34), 123 (30), 121 (25), 119
(30), 111 (21), 109 (21), 107 (33), 105 (23), 95 (100), 93 (38), 91 (32), 81 (63), 79 (34), 77 (23),
69 (30), 67 (25), 65 (11), 55 (22), 53 (15), 41 (37).
.
8,8-Dimethyl-3,4,5,6,7,8-hexahydro-1H-isochromene 8. BF3 OEt2 (0.49 g, 0.44 ml, 3.38 mmol)
was added dropwise to a soln. of 7 (5.62 g, 33.7 mmol) in CH2Cl2 (100 ml) at 20°C. After 96 h at
20°C the reaction mixture was poured onto sat. aq. NaHCO3 (100 ml). The aq. phase was
extracted with Et2O (3 x 50 ml), and the combined org. phase was washed with H2O (50 ml),
brine (50 ml), then dried (Na2SO4) and concentrated in vacuo. The residual oil was purified by
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CC/SiO2 (cyclohexane/AcOEt 99:1 to 95:5) to afford pure 8 in 47% yield. Alternatively, a
mixture of -pyronene 3 (30g, 220 mmol), paraformaldehyde (7.27g, 242 mmol) and AcOH
(56.9g, 947 mmol) was heated at 130°C for 5 h. After 85% conversion the cold reaction mixture
was poured onto H2O/ice (100 ml), then extracted with Et2O (3 x 100 ml). The org. phase was
carefully washed with sat. aq. NaHCO3, then with H2O, and brine to neutrality. The org. phase
was dried (Na2SO4), and concentrated in vacuo. Purification of a 9:1 mixture of 8/16 by CC/SiO2
(cyclohexane/AcOEt 99:1 to 95:5) afforded 8 in 38% yield. IR: 2956, 2928, 2903, 2867, 2846,
2830, 1742, 1457, 1433, 1382, 1361, 1238, 1161, 1130, 1097, 1038, 1024, 988, 935, 890, 817,
1
696. H-NMR: 4.08 (quint, J = 2.4, 2H); 3.74 (t, J = 5.7, 2H); 1.98-1.95 (m, 2H); 1.89-1.86 (m,
2H); 1.66-1.62 (m, 2H); 1.46-1.44 (m, 2H); 0.99 (s, 6H). 13C-NMR: 134.1 (s); 125.1 (s); 64.9 (t);
64.8 (t); 39.6 (t); 32.3 (s); 30.5 (t); 29.9 (t); 27.5 (2q); 19.1 (t). MS: 166 (30, M+.), 151 (100), 123
(12), 121 (23), 109 (33), 96 (28), 93 (26), 91 (15), 81 (10), 79 (21), 77 (12), 67 (10), 41 (11).
Woody, camphoraceous, terpenic, dusty.
2-(2,3,3-Trimethylcyclohex-1-en-1-yl)ethan-1-ol 9. Li (15.1 mg, 2.18 mmol) was added
portionwise to a soln. of 8 (330 mg, 1.98 mmol) in H2NCH2CH2NH2 (1.35 ml). Two
supplementary portion of Li were added after 24 and 48h. After a total of 67h the reaction
mixture was poured into satd. aq. NH4Cl (10 ml) and extracted with Et2O (3 x 10 ml). The org.
phase was washed with H2O, dried (Na2SO4), and concentrated in vacuo. Purification by
CC/SiO2 (cyclohexane/AcOEt 8:2) afforded pure 9 in 69% yield. IR: 3323, 2955, 2926, 2907,
1
2865, 1456, 1384, 1373, 1359, 1204, 1084, 1039, 1023, 616. H-NMR: 3.63 (brdt, J = 4.0, 6.5,
2H); 2.28 (t, J = 6.5, 2H); 1.95 (tq, J = 1.5, 6.2, 2H); 1.63 (t, J = 1.5, 3H); 1.60-1.56 (m, 2H);
1.45-1.42 (m, 2H); 1.40 (brt, J = 4.0, 1OH); 1.00 (s, 6H). 13C-NMR: 136.9 (s); 125.6 (s); 61.0 (t);
39.5 (t); 37.2 (t); 34.7 (s); 30.7 (t); 28.2 (2q); 19.5 (t); 13.4 (q). MS: 168 (56, M+.), 153 (100),
135 (30), 123 (73), 109 (86), 107 (63), 105 (14), 95 (30), 93 (48), 91 (36), 81 (48), 79 (40), 77
(21), 69 (18), 67 (26), 55 (23), 43 (19), 41 (29). Woody, cedar, phenolic, pyrogenous.
7,7,7a-Trimethyloctahydrobenzofuran 10. MeSO3H (151 mg, 1.57 mmol) was added dropwise to
a soln. of 9 (220 mg, 1.307 mmol) in CH2Cl2 (15 ml) at 20°C. After 15 min. the reaction mixture
was poured into sat. aq. NaHCO3. After separation and extraction of the aq. phase with Et2O (3 x
10 ml), the org. phase was washed with H2O, brine, dried (Na2SO4), concentrated, to afford
quantitatively a 87:13 trans-/cis-10 mixture. Purification by CC/SiO2 (cyclohexane/AcOEt 99:1)
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afforded trans-10 (64% yield), and cis-10 (1.4% yield). Trans-stereoisomer Rf = 0.23 (99:1
cyclohexane/AcOEt). IR: 2952, 2926, 2872, 1477, 1459, 1451, 1438, 1386, 1363, 1171, 1148,
1
1126, 1096, 1072, 1035, 1016, 1004, 985, 942, 918, 888, 864, 735. H-NMR: 3.93 (q, J = 8.3,
1H); 3.87 (dt, J = 2.8, 9.2, 1H); 2.24-2.18 (m, 1H); 1.88 (dt, J = 6.1, 12.2, 1H); 1.59 (dt, J = 4.4,
12.2, 1H); 1.56-1.52 (m, 1H); 1.50-1.39 (m, 3H); 1.13-1.08 (m, 2H); 1.02 (s, 3H); 0.99 (s, 3H);
0.94 (s, 3H). 13C-NMR: 85.9 (s); 63.9 (t); 40.3 (d); 36.8 (t); 35.6 (s); 32.4 (t); 30.0 (t); 25.7 (2q);
20.6 (t); 19.3 (q). MS: 168 (12 M+.), 153 (10), 97 (100), 95 (20), 84 (10), 55 (9), 43 (22), 41 (11).
Cis-stereoisomer Rf = 0.30 (99:1 cyclohexane/AcOEt).1H-NMR: 3.82 (dt, J = 2.0, 9.1, 1H); 3.74
(q, J = 8.1, 1H); 1.94-1.88 (m, 1H); 1.86-1.81 (m, 1H); 1.76-1.66 (m, 2H); 1.59-1.53 (m, 1H);
1.51-1.42 (m, 1H); 1.39 (dt, J = 4.6, 13.7, 1H); 1.31-1.23 (m, 1H); 1.17-1.12 (m, 1H); 1.01 (s,
3H); 0.98 (s, 3H); 0.97 (s, 3H). 13C-NMR: 84.7 (s); 64.4 (t); 41.1 (d); 37.9 (s); 37.6 (t); 29.7 (t);
28.6 (t); 26.1 (q); 23.0 (t); 20.4 (q); 15.1 (q). MS: 168 (9, M+.), 153 (7), 97 (100), 95 (18), 84
(11), 55 (10), 43 (27) ; 41 (13), 28 (30). Camphoraceous, sulfury, blackcurrant.
(E)-4-(4,8-Dimethylnona-3,7-dien-1-yl)-3,6-dihydro-2H-pyran 11. A mixture of 2 (40g, 196
mmol), paraformaldehyde (12.94 g, 430 mmol) and AcOH (50.5g, 842 mmol) was heated at
130°C for 52h. The cold reaction mixture was poured into H2O/ice (200 ml) and extracted with
Et2O (3 x 100 ml). The org. phase was carefully washed with sat. aq. NaHCO3, and H2O, and
brine, then dried (Na2SO4), and concentrated in vacuo. Two successive purifications by CC/SiO2
(cyclohexane/AcOEt 99:1 to 95:5) afforded 11 in 15% yield.33) IR: 2964, 2919, 2850, 1742,
1673, 1646, 1594, 1448, 1382, 1376, 1233, 1128, 1034, 990, 971, 892, 849. 1H-NMR: 5.41-5.40
(m, 1H); 5.13-5.08 (m, 2H); 4.12-4.10 (m, 2H); 3.78 (t, J = 5.7, 2H); 2.12 (q, J = 7.1, 2H); 2.07-
13
1.97 (m, 8H); 1.68 (s, 3H); 1.60 (s, 6H). C-NMR: 135.6 (s); 135.4 (s); 131.3 (s); 124.3 (d);
123.8 (d); 119.6 (d); 65.5 (t); 64.4 (t); 39.7 (t); 37.1 (t); 28.6 (t); 26.7 (t); 25.8 (t); 25.7 (q); 17.7
(q); 16.0 (q). MS: 234 (1, M+.), 136 (13), 121 (9), 109 (13), 96 (33), 93 (15), 83 (11), 81 (30), 79
(10), 69 (100), 67 (14), 55 (10), 53 (9), 41 (43). Metallic, very weak.
(6aRS,10aRS)-7,7,10a-Trimethyl-3,4,5,6,6a,7,8,9,10,10a-decahydro-1H-benzo[h]isochromene
.
-12. BF3 OEt2 (0.294 g, 2.03 mmol), was added dropwise to a soln. of 11 (4.75 g, 20.27 mmol)
33
)
An enriched intermediate fraction allowed, after preparative GC purification, to isolate a minor side product
(6% of the crude reaction mixture) corresponding to the acetate of the Prins reaction (see the
Supplementary Material for analytical data).
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in CH2Cl2 (100 ml) at 20°C. After 72 h the reaction mixture was poured into sat. aq. NaHCO3
(100 ml). After separation, the aq. phase was washed with Et2O (3 x 100 ml). The org. phase was
washed with H2O, brine, then dried (Na2SO4), and concentrated in vacuo. Two successive
purifications by CC/SiO2 (cyclohexane/AcOEt 99:1) afforded -12 in 14% yield. Alternatively, a
mixture of 4 (200 mg, 0.979 mmol), paraformaldehyde (32.3 mg, 1.077 mmol) and AcOH (588
mg, 9.79 mmol) was heated at 130°C for 24 h. The cold reaction mixture was poured into
H2O/ice and extracted with Et2O (3 x 10 ml). The org. phase was carefully washed with sat. aq.
NaHCO3, then washed with H2O, and brine, dried (Na2SO4), and concentrated. Purification by
CC/SiO2 (cyclohexane/AcOEt 99:1) afforded -12 in 27% yield. IR: 2923, 2865, 2845, 1742,
1458, 1386, 1375, 1364, 1236, 1161, 1134, 1120, 1093, 1070, 1027, 987, 961, 941, 914, 885,
854, 817, 689. 1H-NMR: 4.13-4.07 (m, 1H); 4.01 (dquint, J = 2.8, 15.7, 1H); 3.88 (ddd, J = 2.8,
6.1, 8.5, 1H); 3.53 (ddd, J = 4.0, 10.0, 10.8, 1H); 2.15-1.86 (m, 4H); 1.76-1.39 (m, 6H); 1.20 (dd,
J = 2.1, 12.4, 1H); 1.13 (ddd, J = 4.0, 13.7, 18.2, 1H); 1.04 (s, 3H); 0.99 (t, J = 4.0, 1H); 0.89 (s,
13
3H); 0.85 (s, 3H). C-NMR: 137.2 (s); 123.9 (s); 64.6 (t); 64.3 (t); 51.5 (d); 41.7 (t); 36.6 (s);
35.8 (t); 33.2 (q); 33.1 (s); 31.7 (t); 29.6 (t); 21.6 (q); 19.7 (q); 18.7 (t); 18.6 (t). MS: 234 (24,
M+.), 219 (33), 149 (10), 123 (10), 119 (10), 109 (22), 105 (10), 96 (100), 91 (14), 69 (11), 41
(10). Woody, amber-like, weak.
(6aRS,10aRS,10bRS)-7,7,10a-Trimethyl-3,4,6,6a,7,8,9,10,10a,10b-decahydro-1H-
benzo[h]isochromene -12. Isolated in analytical amounts during the purification of -12. IR:
2922, 2894, 2865, 2844, 1742, 1459, 1441, 1387. 1375, 1364, 1237, 1160, 1134, 1119, 1105,
1093, 1070, 1027, 987, 961, 914, 884, 855, 828, 815, 688. 1H-NMR: 5.46 (dd, J = 2.1, 5.4, 1H);
3.91 (dd, J = 6.1, 10.9, 1H); 3.74 (dd, J = 1.3, 5.8, 1H); 3.23 (ddd, J = 2.7, 11.1, 13.3, 1H); 3.18
(t, J = 11.1, 1H); 2.37-2.29 (m, 1H); 2.16-2.10 (m, 2H); 2.08-1.96 (m, 2H); 1.89-1.40 (m, 3H);
13
1.22-1.10 (m, 4H); 0.91 (s, 3H); 0.88 (s, 3H); 0.83 (s, 3H). C-NMR: 133.3 (s); 121.1 (d); 68.5
(t); 68.4 (t); 51.5 (d); 49.7 (d); 42.1 (t); 39.8 (t); 34.5 (s); 34.1 (t); 33.6 (q); 32.8 (s); 23.2 (t); 22.3
(q); 18.6 (t); 15.2 (q). MS: 234 (33, M+.), 219 (22), 149 (9), 124 (42), 109 (100), 105 (15), 96
(14), 91 (17), 81 (12), 79 (10), 69 (10), 55 (9), 41 (12).
(4aRS,6aRS,10aRS,10bRS)-7,7,10a-Trimethyldodecahydro-1H-benzo[h]isochromene 13.
A
suspension of -12 (47 mg, 0.201 mmol) and 10% Pd/C (21.34 mg, 0.02 mmol) in EtOH (15 ml)
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was hydrogenated under 1 atm. of H2 for 17 h at 20°C. The reaction mixture was filtered over
Celite®, concentrated, and purified by CC/SiO2 (cyclohexane/AcOEt 99:1) to afford 13 in 88%
yield as a 77:23 mixture of trans/cis stereoisomers. A single fraction reaching 90% purity for the
major trans-diastereoisomer was used for analyses. IR: 2918, 2865, 2843, 1462, 1445, 1387,
1364, 1136, 1094, 999, 983, 954, 865, 657. 1H-NMR: 3.95 (dd, J = 4.2, 10.8, 1H); 3.88 (dd, J =
4.2, 10.8, 1H); 3.29 (ddd, J = 2.3, 11.1, 12.8, 1H); 3.12 (t, J = 11.1, 1H); 1.75 (dq, J = 3.0, 12.4,
1H); 1.61-1.57 (m, 2H); 1.55-1.48 (m, 2H); 1.43-1.37 (m, 2H); 1.34-1.23 (m, 2H); 1.17 (dt, J =
4.2, 13.4, 1H); 1.05-0.98 (m, 4H); 0.91 (dd, J = 2.3, 12.4, 1H); 0.86 (s, 3H); 0.85 (s, 3H); 0.82 (s,
3H). 13C-NMR: 68.2 (t); 68.1 (t); 55.2 (d); 54.4 (d); 42.0 (t); 38.8 (t); 35.9 (s); 34.8 (t); 34.5 (d);
34.5 (t); 33.5 (q); 33.2 (s); 21.9 (q); 21.4 (t); 18.7 (t); 15.0 (q). MS: 236 (96, M+.), 221 (100), 203
(11), 177 (18), 151 (41), 135 (16), 123 (85), 121 (17), 109 (45), 107 (22), 105 (11), 96 (46), 95
(36), 93 (25), 91 (17), 83 (40), 81 (31), 79 (23), 77 (10), 69 (27), 67 (26), 55 (28), 41 (29). The
minor (4aSR,6aRS,10aRS,10bRS)-7,7,10a-trimethyldodecahydro-1H-benzo[h]isochromene cis-
stereoisomer exhibits the following analytical data, deduced from the mixture. 1H-NMR: 4.16 (d,
J = 12.0, 1H); 3.98 (dd, J = 4.9, 12.0, 1H); 3.36 (ddd, J = 3.2, 12.0, 15.2, 1H); 3.32 (dd, J = 4.2,
12.0, 1H); 2.06-2.04 (m, 1H); 1.98 (dq, J = 5.0, 13.0, 1H); 1.92-1.86 (m, 1H); 1.69-1.65 (m, 1H);
1.61-1.57 (m, 1H); 1.55-1.48 (m, 1H); 1.43-1.37 (m, 3H); 1.34-1.23 (m, 2H); 1.17 (dt, J = 4.2,
13.4, 1H); 1.05-0.98 (m, 4H); 0.91 (dd, J = 2.3, 12.4, 1H); 1.18 (s, 3H); 0.86 (s, 3H); 0.83 (s,
3H).. 13C-NMR: 68.3 (t); 68.2 (t); 55.7 (d); 49.3 (d); 42.2 (t); 40.3 (t); 38.0 (s); 34.1 (d); 33.7 (t);
33.7 (q); 33.2 (s); 29.8 (t); 21.7 (q); 19.0 (q); 18.4 (t); 18.3 (t). MS: 236 (62, M+.), 221 (37), 203
(17), 177 (17), 151 (12), 135 (14), 123 (100), 121 (24), 109 (37), 107 (19), 105 (100), 96 (25), 95
(35), 93 (21), 91 (14), 83 (53), 81 (31), 79 (20), 69 (23), 67 (21), 55 (25), 41 (23). Woody,
amber-like, weak.
2-((4aRS,8aRS)-1,5,5,8a-Tetramethyl-3,4,4a,5,6,7,8,8a-octahydronaphthalen-2-yl)ethan-1-ol
14. Li (23 mg, 3.35 mmol) was added to a soln. of -12 (392 mg, 1.676 mmol) in MeNH3 (2M in
THF, 8.38 ml, 16.76 mmol) at -78°C. After 18 h, solid NH4Cl (100 mg) was added to the blue
reaction mixture, followed by Et2O (10 ml), and H2O (5 ml). The org. phase was washed with
H2O, brine, dried (Na2SO4), and concentrated in vacuo. Purification by CC/SiO2 (99:1 to 8:2)
afforded 14 in 59% yield. IR: 3323, 2924, 2865, 2850, 1457, 1449, 1379, 1373, 1366, 1083,
1040, 972, 862. 1H-NMR: 3.62 (t, J = 7.0, 2H); 2.30-2.20 (m, 2H); 2.06-2.03 (m, 2H); 1.80 (dt, J
= 3.4, 12.5, 1H); 1.74-1.56 (m, 3H); 1.58 (t, J = 2.0, 3H); 1.50-1.38 (m, 3H); 1.14 (dt, J = 3.5,
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13.2, 1H); 1.10 (dd, J = 2.0, 12.8, 1H); 1.06 (dt, J = 3.5, 13.2, 1H); 0.97 (s, 3H); 0.89 (s, 3H);
0.84 (s, 3H). 13C-NMR: 140.4 (s); 124.3 (s); 61.1 (t); 51.6 (d); 41.6 (t); 38.5 (s); 37.1 (t); 37.0 (t);
33.3 (s); 33.2 (q); 31.8 (t); 21.6 (q); 19.6 (q); 19.1 (t); 19.0 (t); 12.6 (q). MS: 236 (22, M+.), 221
(37), 203 (17), 191 (58), 177 (17), 175 (16), 151 (52), 149 (22), 147 (17), 139 (16), 135 (34), 133
(29), 125 (43), 123 (27), 121 (62), 119 (37), 117 (12), 109 (66), 107 (68), 105 (54), 97 (19), 95
(100), 93 (52), 91 (69), 83 (26), 81 (57), 79 (52), 77 (37), 69 (72), 67 (39), 65 (14), 55 (63), 53
(22), 43 (29), 41 (73), 39 (17), 28 (36).
(5aRS,9aRS)-6,6,9a,9b-Tetramethyldodecahydronaphtho[1,2-b]furan 15. MeSO3H (44.6 mg,
0.465 mmol) was added dropwise to a soln. of 14 (91.5 mg, 0.387 mmol) in CH2Cl2 (10 ml) at
20°C. After 75 min. the reaction mixture was poured into sat. aq. NaHCO3. After separation, the
aq. phase was extracted with Et2O (3 x 10 ml). The org. phase was washed with H2O, brine,
dried (Na2SO4), then concentrated in vacuo. Purification by CC/SiO2 (cyclohexane/AcOEt 95:5)
afforded 15 in 51% yield as a 55:45 mixture of stereoisomer. IR: 2933, 2869, 1459, 1381, 1371,
1
1257, 1241, 1144, 1107, 1086, 1010, 987, 920, 879, 801. H-NMR: 3.95 (q, J = 9.0, 1H); 3.87
(ddd, J = 2.5, 8.5, 10.2, 1H); 2.21-2.15 (m, 1H); 1.91 (dt, J = 6.9, 11.6, 1H); 1.70-1.65 (m, 1H);
1.62-1.57 (m, 1H); 1.52-1.50 (m, 1H); 1.49-1.41 (m, 2H); 1.36-1.32 (m, 1H); 1.29-1.19 (m, 2H);
1.15-1.08 (m, 2H); 1.04-0.92 (m, 2H); 0.99 (s, 3H); 0.98 (s, 3H); 0.88 (s, 3H); 0.86 (s, 3H). 13C-
NMR: 88.0 (s); 64.1 (t); 45.4 (d); 41.5 (t); 39.9 (s); 39.9 (d); 33.9 (q); 33.5 (t); 33.1 (s); 32.3 (t);
30.8 (t); 22.5 (q); 21.1 (t); 18.7 (2q); 18.6 (t). MS: 236 (21, M+.), 97 (100), 84 (8), 43 (8), 41 (6).
Animal, naphtaline, ambrinol, buttery, very weak.
5,5-Dimethyl-3,4,5,6,7,8-Hexahydro-1H-isochromene 16. Obtained in analytical amount during
the CC/SiO2 purification of a 9:1 mixture of 8/16 (see above 8). IR: 2956, 2928, 2902, 2866,
2846, 2830, 1741, 1458, 1432, 1382, 1360, 1333, 1295, 1267, 1239, 1222, 1161, 1119, 1097,
1
1023, 995, 988, 953, 935, 891, 864, 817, 695. H-NMR: 3.89 (brs, 2H); 3.77 (t, J = 5.7, 2H);
13
2.06-2.03 (m, 2H); 1.75-1.72 (m, 2H); 1.67-1.61 (m, 2H); 1.49-1.46 (m, 2H); 0.98 (s, 6H). C-
NMR: 133.0 (s); 126.3 (s); 68.6 (t); 65.4 (t); 39.1 (t); 33.1 (s); 27.3 (2q); 26.0 (t); 23.8 (t); 18.8
(t). MS: 166 (91, M+.), 151 (99), 123 (23), 121 (14), 110 (46), 109 (38), 107 (18), 105 (15), 97
(100), 95 (20), 93 (28), 91 (26), 81 (29), 79 (32), 77 (21), 69 (18), 67 (20), 55 (17), 53 (11), 43
(18), 41 (23), 39 (14). Potato, cellar.
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(Z)-(6-ethylidene-2,2-Dimethylcyclohexyl)methanol 17. Li (0.183g, 26.3 mmol) was added
portionwise to a soln. of 8 (2.19 g, 13.17 mmol) in MeNH2 (2M in THF, 65.9 ml, 132 mmol) at -
78°C. After 2h and persistent blue color, the MeNH2 was allowed to evaporate and solid NH4Cl
(3.0 g) was added. The reaction mixture was partitioned between Et2O (50 ml) and H2O (50 ml),
and the org. phase was washed with H2O (50 ml), then brine (50 ml), dried (Na2SO4), and
concentrated. Purification by CC/SiO2 (cyclohexane/AcOEt 99:1 to 8:2) afforded 9 in 10% yield,
as well as 17 in 10% yield. IR: 3349, 2950, 2925, 2865, 1455, 1383, 1363, 1118, 1032, 973, 933,
1
907, 819, 624. H-NMR: 5.62 (dq, J = 1.5, 6.2, 1H); 3.71 (dt, J = 5.3, 9.7, 1H); 3.65 (brt, J =
10.3, 1H); 2.56 (dd, J = 5.6, 10.9, 1H); 2.38-2.25 (m, 1H); 2.12-2.06 (m, 1H); 2.03-1.99 (m, 1H);
1.70-1.56 (m, 1H); 1.62 (dd, J = 2.0, 6.8, 3H); 1.49 (tt, J = 3.5, 13.5, 2H); 1.35-1.20 (m, 1H);
13
0.93 (s, 3H); 0.90 (s, 3H). C-NMR: 137.4 (s); 123.0 (d); 60.4 (t); 48.7 (d); 35.2 (t); 33.7 (s);
31.7 (t); 28.8 (q); 27.7 (q); 23.5 (t); 12.8 (q). MS: 168 (8, M+.), 150 (22), 137 (78), 135 (28), 123
(55), 121 (23), 109 (50), 107 (62), 105 (12), 95 (86), 93 (43), 91 (37), 83 (17), 81 (100), 79 (63),
77 (31); 69 (73), 67 (51), 65 (13), 57 (12), 55 (43), 53 (23), 43 (23), 41 (57), 39 (26), 28 (38).
Earthy, camphoraceous.
4,4,7a-Trimethyloctahydrobenzofuran 19. MeSO3H (28.8 mg, 0.3 mmol) was added to a soln. of
18 (500 mg, 2.98 mmol) in CH2Cl2 (10 ml). After 4 h at 20°C the reaction mixture was poured
into H2O/ice (10 ml), and the aq. phase was extracted with Et2O (2 x 10 ml). The org. phase was
washed with sat. aq NaHCO3, H2O, brine, dried (Na2SO4), and concentrated. Bulb-to-bulb
distillation afforded 19 in 69% yield as a 83:17 trans/cis mixture. B.p.: 115°C/ 2 mbar. Further
purification by CC/SiO2 (cyclohexane/AcOEt 99:1 to 95:5) afforded analytically pure material.
Trans-stereoisomer IR: 2933, 2867, 1456, 1374, 1256, 1243, 1206, 1157, 1111, 1091, 1077,
1068, 1047, 1006, 956, 949, 937, 855. 1H-NMR: 3.88 (dt, J = 2.7, 8.6, 1H); 3.80 (q, J = 8.1, 1H);
1.89-1.80 (m, 2H); 1.78-1.64 (m, 2H); 1.52 (tt, J = 3.4, 13.4, 1H); 1.49-1.26 (m, 3H); 1.14 (dt, J
13
= 4.5, 13.4, 1H); 1.07 (s, 3H); 0.96 (s, 3H); 0.85 (s, 3H). C-NMR: 79.9 (s), 64.0 (t); 56.4 (d);
41.1 (t); 38.7 (t); 33.1 (s); 32.8 (q); 23.6 (t); 21.2 (t); 20.0 (2q). MS: 168 (0, M+.), 153 (100), 125
1
(34), 198 (9), 97 (9), 95 (17), 85 (12), 69 (30), 55 (13), 43 (17), 41 (12). cis-Stereoisomer H-
NMR: 3.83-3.79 (m, 1H); 3.76 (dd, J = 8.4, 16.9, 1H); 1.96-1.91 (m, 2H); 1.60 (t, J = 9.4, 1H);
13
1.56-1.33 (m, 5H); 1.32 (s, 3H); 1.17 brdd, J = 3.5, 11, 1H); 1.02 (s, 3H); 0.92 (s, 3H). C-
NMR: 80.8 (s); 63.9 (t); 54.0 (d); 34.5 (t); 33.7 (t); 32.4 (s); 30.4 (q); 29.4 (t); 28.7 (q); 27.1 (q);
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20.0 (t). MS: 168 (2, M+.), 153 (50), 125 (100), 95 (9), 84 (9), 69 (16), 55 (10), 43 (23), 41 (12).
Chemical, solvent.
3,4,5,6,7,8-Hexahydro-1H-5,8-methanoisochromene 20. A soln. of 5 (224 mg, 1.872 mmol),
paraformaldehyde (62 mg, 2.06 mmol) and SnCl4 (24 mg, 0.094 mmol) in CH2Cl2 (10 ml) was
stirred for 72 h at 20°C. The reaction mixture was poured into H2O/ice (5 ml). The aq. phase was
extracted with Et2O (3 x 10 ml). The org. phase was washed with sat. aq. NaHCO3, H2O, brine,
dried (Na2SO4), then concentrated. Purification by CC/SiO2 (cyclohexane/AcOEt 99:1 to 95:5)
afforded 20 in 22% yield. Rf = 0.44 (cyclohexane/AcOEt 95:5). IR: 2953, 2917, 2867, 2830,
1456, 1447, 1427, 1386, 1299, 1277, 1225, 1147, 1090, 1063, 962, 936, 884, 836, 678. 1H-NMR:
4.30 (dt, J = 2.5, 15.4, 1H); 4.02 (dt, J = 2.5, 15.4, 1H); 3.73 (ddd, J = 4.4, 6.6, 11.0, 1H); 3.62
(dt, J = 5.5, 11.0, 1H); 2.71 (brs, 1H); 2.69 (brs, 1H); 2.21-2.15 (m, 1H); 2.11-2.05 (m, 1H); 1.65
(dd, J = 2.0, 9.0, 2H); 1.35 (dquint, J = 2.0, 8.0, 1H); 1.09 (dt, J = 1.6, 8.0, 1H); 1.05 (dt, J = 2.2,
13
10.0, 2H). C-NMR: 138.2 (s); 137.1 (s); 64.6 (t); 64.5 (t); 46.4 (t); 44.9 (d); 42.5 (d); 26.2 (t);
26.0 (t); 24.4 (t). MS: 150 (40, M+.), 122 (48), 121 (31), 109 (21), 105 (18), 92 (68), 91 (100), 79
(27), 77 (25), 65 (15), 51 (10), 41 (9), 39 (16). Woody, dusty, cellar.
7a-Methyloctahydro-4,7-methanobenzofuran 22. MeSO3H (174 mg, 1.811 mmol) was added to a
soln. of 21 (230 mg, 1.509 mmol) in CH2Cl2 (15 ml) at 20°C. After 30 min. the reaction mixture
was poured into sat. aq. NaHCO3 (10 ml). The aq. phase was extracted with Et2O (3 x 10 ml).
The org. phase was washed with H2O, brine, dried (Na2SO4), then concentrated. Purification by
CC/SiO2 (cyclohexane/AcOEt 99:1) afforded 22 in 48% yield as a 79:21 endo/exo mixture. A
second CC/SiO2 afforded the pure endo stereoisomer in 18% yield. Rf = 0.15
1
(cyclohexane/AcOEt 99:1). IR: 2953, 2922, 2853, 1459, 1376, 1260, 1070, 886, 802, 722. H-
NMR: 4.02 (dt, J = 5.0, 8.7, 1H); 3.95 (q, J = 7.7, 1H); 2.17 (brt, J = 4.5, 1H); 2.08-2.07 (m, 1H);
1.89-1.83 (m, 1H); 1.80-1.72 (m, 2H); 1.65 (dquint, J = 1.5, 10, 1H); 1.53-1.48 (m, 2H); 1.45
13
(brt, J = 1.5, 1H); 1.43 (brt, J = 1.5, 1H); 1.41-1.36 (m, 1H); 1.25 (s, 3H). C-NMR: 90.5 (s);
71.5 (t); 51.5 (d); 48.3 (d); 41.9 (t); 41.2 (d); 26.8 (q); 26.7 (t); 22.2 (t); 22.1 (t). MS: 152 (1,
M+.), 137 (10), 123 (15), 97 (8), 84 (100), 79 (8), 67 (12), 43 (33). Odourless.
5-(2,6,6-Trimethylcyclohex-1-en-1-yl)pent-1-en-3-one 23e. A suspension of 24b (640 mg, 3.06
mmol) and MnO2 (5310 mg, 61.1 mmol) in CH2Cl2 (30 ml) was stirred for 18h at 20°C. The
reaction mixture was filtered over Celite®, and concentrated. Purification by CC/SiO2
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(cyclohexane/AcOEt 99:1) afforded 23e in 34% yield. IR: 2927, 2907, 2865, 2829, 1700, 1681,
1
1616, 1472, 1457, 1399, 1360, 1261, 1203, 1184, 1093, 984, 958, 763. H-NMR: 6.36 (dd, J =
10.5, 17.6, 1H); 6.22 (dd, J = 1.4, 17.6, 1H); 5.82 (dd, J = 1.4, 10.5, 1H); 2.68-2.63 (m, 2H); 2.3
(dd, J = 8.2, 9.1, 2H); 1.91 (t, J = 5.9, 2H); 1.61-1.54 (m, 2H); 1.59 (s, 3H); 1.44-1.41 (m, 2H);
0.99 (s, 6H). 13C-NMR: 200.8 (s); 136.6 (d); 136.2 (s); 128.0 (s); 127.7 (t); 40.4 (t); 39.8 (t); 35.1
(s); 32.8 (t); 28.5 (2q); 22.5 (t); 19.8 (q); 19.5 (t). MS: 206 (2, M+.), 188 (18), 173 (20), 136 (27),
123 (27), 121 (100), 119 (22), 109 (10), 107 (23), 95 (28), 93 (65), 91 (24), 81 (29), 79 (32), 77
(19), 69 (12), 67 (14), 55 (60), 41 (25). Odourless.
5-(2,6,6-Trimethylcyclohex-1-en-1-yl)pent-1-yn-3-one 23f. A suspension of 24c (976 mg, 4.73
mmol) and MnO2 (8230 mg, 95 mmol) in CH2Cl2 (50 ml) was stirred for 25h at 20°C. The
reaction mixture was filtered over Celite®, and concentrated. Purification by CC/SiO2
(cyclohexane/AcOEt 99:1) afforded 23f in 41% yield. IR: 2928, 2907, 2866, 2830, 2091, 1679,
1472, 1457, 1404, 1381, 1361, 1280, 1262, 1221, 1191, 1175, 1099, 1042, 1018, 998, 752, 688,
641. 1H-NMR: 3.24 (s, 1H); 2.68-2.65 (m, 2H); 2.37-2.34 (m, 2H); 1.91 (t, J = 6.5, 2H); 1.59 (s,
13
3H); 1.58-1.55 (m, 2H); 1.43-1.41 (m, 2H); 0.99 (s, 6H). C-NMR: 187.3 (s); 135.1 (s); 128.6
(s); 81.4 (s); 78.4 (d); 46.2 (t); 39.7 (t); 35.0 (s); 32.7 (t); 28.4 (2q); 22.3 (t); 19.7 (q); 19.4 (t).
MS : 204 (7, M+.), 189 (26), 171 (42), 161 (17), 156 (12), 147 (23), 143 (14), 136 (27), 133 (21),
131 (11), 129 (10), 123 (40), 121 (100), 119 (42), 109 (11), 107 (26), 105 (40), 95 (20), 93 (51),
91 (45), 81 (30), 79 (38), 77 (26), 69 (11), 67 (16), 65 (10), 55 (22), 53 (37), 41 (26). Ionone-
like, weak.
5-(2,6,6-Trimethylcyclohex-1-en-1-yl)pent-1-en-3-ol 24b. Freshly prepared vinylMgBr
(1M/THF, 2.78 ml, 2.78 mmol) was added dropwise at 0°C to a soln. of 23d (478 mg, 2.65
.
mmol) and LaCl3 2LiCl (0.6M/THF, 0.883 ml, 0.53 mmol) in THF (20 ml). After 0.5h, the
reaction mixture was poured into sat. aq. NH4Cl (10 ml). The aq. phase was extracted with Et2O
(3 x 10 ml). The org. phase was washed with brine, dried (Na2SO4), then concentrated.
Purification by CC/SiO2 (cyclohexane/AcOEt 9:1) afforded 24b in 42% yield besides 24a.
Alternatively, a soln. of 24c (1.3g, 6.3 mmol) in THF (30 ml) was added dropwise to a
suspension of LiAlH4 (0.239 g, 6.3 mmol) in THF (20 ml) at 0°C. After 8d at 20°C, 10% aq.
NaOH (15 ml) was added. The aq. phase was extracted with Et2O (3 x 10 ml). The org. phase
was washed with H2O, brine, dried (Na2SO4), then concentrated. Purification by CC/SiO2+3%
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AgNO3 (cyclohexane/AcOEt 99:1) afforded 24b in 49% yield. IR: 3311, 2926, 2865, 2829,
1472, 1457, 1431, 1381, 1360, 1277, 1203, 1169, 1116, 1051, 989, 919, 734, 647, 622. 1H-NMR:
5.90 (ddd, J = 5.3, 10.5, 17.5, 1H); 5.24 (dt, J = 1.2, 17.5, 1H); 5.13 (dt, J = 1.2, 10.5, 1H); 4.10
(brq, J = 5.3, 1H); 2.22-2.05 (m, 2H); 2.00-1.92 (m, 1H); 1.90 (t, J = 6.5, 2H); 1.63-1.54 (m, 3H);
13
1.59 (s, 3H); 1.43-1.40 (m, 2H); 1.01 (d, J = 5.3, 1OH); 0.99 (s, 3H); 0.98 (s, 3H). C-NMR:
141.1 (d); 136.7 (s); 127.2 (s); 114.7 (t); 73.9 (d); 39.8 (t); 37.5 (t); 35.0 (s); 32.7 (t); 28.6 (2q);
24.3 (t); 19.8 (q); 19.5 (t). MS: 208 (M+.), 175 (20), 136 (13), 133 (12), 125 (30), 123 (100), 121
(39), 119 (21), 109 (22), 107 (27), 105 (21), 97 (12), 95 (52), 93 (38), 91 (31), 81 (48), 79 (31),
77 (18), 69 (26), 67 (25), 57 (19), 55 (25), 53 (11), 41 (23). Woody, weak.
5-(2,6,6-Trimethylcyclohex-1-en-1-yl)pent-1-yn-3-ol 24c. EthynylMgBr (0.5M/THF, 10.6 ml, 5.3
mmol) was added dropwise to a soln. of 23d (956 mg, 5.3 mmol) in Et2O (20 ml) at 0°C. After
18h at 20°C, the reaction mixture was poured into sat. aq. NH4Cl (10 ml). The aq. phase was
extracted with Et2O (3 x 10 ml). The org. phase was washed with H2O, brine, dried (Na2SO4),
then concentrated in vacuo. Purification by CC/SiO2 (cyclohexane/AcOEt 9:1) afforded 24c in
94% yield. IR: 3309, 2954, 2926, 2906, 2865, 2829, 1473, 1456, 1440, 1381, 1360, 1203, 1059,
1041, 1014, 997, 973, 937, 889, 652, 624. 1H-NMR: 4.37 (dq, J = 2.1, 6.5, 1H); 2.50 (d, J = 2.1,
1H); 2.21-2.11 (m, 2H); 2.00 (d, J = 5.3, 1H); 1.90 (t, J = 6.5, 2H); 1.81-1.77 (m, 2H); 1.61 (s,
13
3H); 1.59-1.55 (m, 2H); 1.43 (s, 1OH); 1.42-1.40 (m, 1H); 1.00 (s, 6H). C-NMR: 136.1 (s);
127.6 (s); 84.9 (s); 73.0 (d); 62.6 (d); 39.8 (t); 37.9 (t); 35.0 (s); 32.8 (t); 28.6 (2q); 23.9 (t); 19.8
(q); 19.5 (t). MS: 206 (1, M+.), 191 (7), 173 (11), 150 (13), 145 (13), 135 (17), 133 (10), 131
(13), 123 (100), 121 (23), 119 (14), 117 (13), 109 (17), 107 (22), 105 (20), 95 (35), 93 (28), 91
(31), 81 (40), 79 (27), 77 (18), 69 (16), 67 (18), 55 (26), 53 (11), 41 (22).
(E)-3-(4,8-Dimethylnona-3,7-dien-1-yl)-2,5-dihydrothiophene 1,1-dioxide 26. Freshly distilled
farnesene 2 (1.0 g, 4.84 mmol) was added to a soln. of DABSO (1.285 g, 5.09 mmol) in MeCN
.
(6 ml) at 20°C. After 15 min., BF3 OEt2 (2.105 g, 1.88 ml, 14.53 mmol) was added at 0°C. After
15 min. at 20°C and 19h at 50°C, the solvent was concentrated and the residue was purified by
CC/SiO2 (cyclohexane/AcOEt 9:1) to afford a 2:1 mixture of 26/27 in 36% yield. A second
purification by CC/SiO2 (cyclohexane/AcOEt 99:1 to 9:1) afforded pure 26 in 13% yield, as well
as pure 27 in 2% yield, besides a mixture of both in 13% yield. Rf = 0.28 (cyclohexane/AcOEt
85 :15). IR: 2964, 2921, 2854, 1667, 1646, 1444, 1403, 1376, 1309, 1232, 1140, 1119, 1026,
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984, 908, 781, 706, 630, 608. 1H-NMR: 568 (brs, 1H); 5.08 (t, J = 6.3, 2H); 3.79 (brs, 2H); 3.68
(brs, 2H); 2.21 (dt, J = 6.3, 7.3, 2H); 2.18 (quint, J = 7.3, 2H); 2.06 (quint, J = 7.3, 2H); 1.99 (t, J
13
= 7.3, 2H); 1.68 (s, 3H); 1.61 (s, 3H); 1.60 (s, 3H). C-NMR: 138.5 (s); 136.9 (s); 131.6 (s);
124.1 (d); 122.3 (d); 117.1 (d); 57.9 (t); 57.0 (t); 39.6 (t); 33.1 (t); 26.6 (t); 25.7 (q); 25.4 (t); 17.7
(q); 16.1 (q). MS: 268 (0, M+.), 204 (7), 161 (22), 133 (38), 120 (27), 107 (14), 105 (11), 93 (70),
91 (24), 81 (22), 79 (27), 77 (15), 69 (100), 67 (26), 55 (16), 53 (14), 41 (54).
3-(2-(2,6,6-Trimethylcyclohex-1-en-1-yl)ethyl)-2,5-dihydrothiophene 1,1-dioxide 27. See above
.
for analytically pure material. Alternatively, BF3 OEt2 (181 mg, 0.162 ml, 1.252 mmol) was
added dropwise to a soln. of a 2:1 mixture of 26/27 (168 mg, 0.626 mmol) in MeCN (6 ml) at
0°C. After 1.5 h at 0°C, the reaction mixture was poured into sat. aq. NaHCO3 (15 ml) and
extracted with Et2O (3 x 15 ml). The org. phase was washed with H2O, brine, dried (Na2SO4),
and concentrated. Purification by CC/SiO2 (cyclohexane/AcOEt 99:1 to 9:1) afforded a 2:1
.
mixture of 27/28 in 66% yield. Alternatively, BF3 OEt2 (180 mg, 0.161 ml, 1.244 mmol) was
added dropwise to a soln. of 26 (167 mg, 0.622 mmol) in MeCN (6 ml) at 0°C. After 1 h at 0°C,
the reaction mixture was poured into sat. aq. NaHCO3 (15 ml) and extracted with Et2O (3 x 15
ml). The org. phase was washed with H2O, brine, dried (Na2SO4), and concentrated. Purification
by CC/SiO2 (cyclohexane/AcOEt 99:1 to 9:1) afforded a 4:1 mixture of 27/26 in 68% yield. Rf =
0.32 (cyclohexane/AcOEt 85 :15). IR: 2925, 2865, 1472, 1456, 1440, 1403, 1380, 1360, 1310,
1
1245, 1232, 1140, 1119, 908, 782, 707, 612. H-NMR: 5.71 (s, 1H); 3.81 (s, 2H); 3.72 (s, 2H);
2.33-2.18 (m, 2H); 2.16-2.12 (m, 2H); 1.91 (t, J = 6.9, 2H); 1.70-1.66 (m, 1H); 1.61-1.55 (m,
13
1H); 1.58 (s, 3H); 1.43-1.41 (m, 2H); 0.98 (s, 6H). C-NMR: 139.0 (s); 135.7 (s); 128.3 (s);
116.3 (d); 57.8 (t); 57.1 (t); 39.6 (t); 34.9 (s); 33.5 (t); 32.7 (t); 28.5 (2q); 25.9 (t); 19.8 (q); 19.4
(t). MS: 268 (0, M+.), 204 (12), 189 (28), 148 (12); 137 (28), 133 (33), 123 (28), 121 (21), 119
(27), 111 (19), 109 (19), 107 (31), 105 (21), 95 (100), 93 (40), 91 (36), 81 (56), 79 (36), 77 (21),
69 (28), 67 (23), 65 (11), 55 (21), 41 (34).
(5aRS,9aRS)-6,6,9a-Trimethyl-1,3,4,5,5a,6,7,8,9,9a-decahydronaphtho[1,2-c]thiophene
2,2-
.
dioxide 28. BF3 OEt2 (107 mg, 0.095 ml, 0.738 mmol) was added dropwise to a soln. of 26 (66
mg, 0.246 mmol) and AcOH (29.5 mg, 0.492 mmol) in CH2Cl2 (10 ml) at 0°C. After 30 min. at
20°C and 9h at 30°C, the cold reaction mixture was poured onto sat. aq. NaHCO3 (10 ml). The
aq. phase was extracted with Et2O (3 x 10 ml). The org. phase was washed with brine, dried
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(Na2SO4), and concentrated in vacuo. Purification by CC/SiO2 (cyclohexane/AcOEt 99:1 to 9:1)
afforded 28 in 47% yield. Rf = 0.18 (cyclohexane/AcOEt 9:1). IR: 2923, 1866, 2847, 1457,
1442, 1388, 1366, 1304, 1248, 1235, 1217, 1142, 1108, 1020, 972, 894, 803, 784, 699, 633. 1H-
NMR: 3.74-3.71 (m, 4H); 2.13-2.10 (m, 1H); 1.83-1.79 (m, 1H); 1.66-1.44 (m, 6H); 1.26-1.18
13
(m, 2H); 1.15 (dd, J = 3.8, 10.4, 1H); 1.05 (s, 3H); 0.92 (s, 3H); 0.87 (s, 3H). C-NMR: 138.8
(s); 126.2 (s); 60.0 (t); 56.5 (t); 51.1 (d); 41.4 (t); 37.1 (t); 36.7 (s); 33.2 (s); 33.0 (q); 27.9 (t);
21.4 (q); 19.3 (q); 18.5 (t); 18.1 (t). MS: 268 (3, M+.), 124 (77), 109 (100), 105 (12), 93 (10), 91
(18), 81 (10), 79 (12), 69 (10), 41 (11).
(2E,6E)-N-ethyl-N,3,7,11-tetramethyldodeca-2,6,10-trien-1-amine 29e. (E)--Farnesene was
treated with ethylmethylamine and nBuLi in THF according to the procedure described for 29b
in [77] to afford 29e in 63% yield. IR: 2967, 2924, 2855, 2786, 1668, 1447, 1380, 1326, 1296,
1
1268, 1221, 1196, 1170, 1132, 1106, 1060, 1038, 981, 962, 939, 886, 830, 803. H-NMR: 5.27
(brt, J = 6.8, 1H); 5.13-5.08 (m, 2H); 2.96 (d, J = 6.05, 2H); 2.41 (q, J = 10.2, 2H); 2.20 (s, 3H);
2.13-2.10 (m, 2H); 2.08-2.02 (m, 4H); 1.98-1.95 (m, 2H); 1.68 (s, 3H); 1.64 (s, 3H); 1.60 (s, 6H);
13
1.08 (t, J = 7.0, 3H). C-NMR: 138.3 (s); 135.2 (s); 131.3 (s); 124.4 (d); 124.0 (d); 121.5 (d);
54.9 (t); 51.1 (t); 41.4 (q); 39.8 (t); 39.7 (t); 26.8 (t); 26.4 (t); 25.7 (q); 17.7 (q); 16.4 (q); 16.0
(q); 12.6 (q). MS: 263 (7, M+.), 194 (46), 126 (24), 112 (100), 81 (11), 72 (29), 69 (23), 58 (10),
44 (10), 41 (16). For the analytical data of a regioisomer side product, see the Supplementary
Material.
1-((2E,6E)-3,7,11-Trimethyldodeca-2,6,10-trien-1-yl)pyrrolidine 29f. (E)--Farnesene was
treated with pyrrolidine and nBuLi in THF according to the procedure described for 29b in [77]
to afford 29f in 62% yield. IR: 2964, 2924, 2874, 2855, 2777, 1669, 1444, 1376, 1347, 1312,
1291, 1264, 1232, 1202, 1138, 1108, 1032, 984, 962, 883, 834, 741. 1H-NMR: 5.33 (brt, J = 6.7,
1H); 5.13-5.08 (m, 2H); 3.09 (d, J = 7.0, 2H); 2.51 (brt, J = 5, 4H); 2.13-1.95 (m, 4H); 1.79-1.76
(m, 8H); 1.68 (s, 3H); 1.65 (s, 3H); 1.60 (s, 6H). 13C-NMR: 137.5 (s); 135.1 (s); 131.3 (s); 124.4
(d); 124.0 (d); 121.8 (d); 54.0 (2t); 53.4 (t); 39.7 (2t); 26.8 (t); 26.4 (t); 25.7 (q); 23.5 (2t); 17.7
(q); 16.4 (q); 16.0 (q). MS: 275 (7, M+.), 208 (11), 206 (47), 138 (18), 124 (100), 122 (10), 84
(50), 81 (11), 70 (25), 69 (20), 55 (10), 41 (18). For the analytical data of a regioisomer side
product, see the Supplementary Material.
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.
(E)-N,N-Diethyl-3-methyl-5-(2,6,6-trimethylcyclohex-1-en-1-yl)pent-2-en-1-amine 30. BF3 OEt2
(15.19 g, 13.56 ml, 105 mmol) was added dropwise to a soln. of 29b (9.712 g, 35 mmol) and
AcOH (4.20g, 69.9 mmol) in CH2Cl2 (100 ml) at 0°C. After 1 h at 0°C and 9 h at 30°C, the
reaction mixture was poured into sat. aq. NaHCO3 (200 ml). The basic aq. phase was extracted
with Et2O (3 x 100 ml). The org. phase was washed with brine, dried (Na2SO4), and concentrated
to afford quantitatively a 26:58:16 mixture of 30/31g/31a. Purification by CC/SiO2
(cyclohexane/AcOEt 6:4 to 1:1) followed, for the combined non-polar fractions, by a second
CC/SiO2 (cyclohexane/AcOEt 99:1 to 9:1) afforded 30 in 17% yield, besides pure 31g and a
mixture of 31g/31a (vide infra). Alternatively, MeSO3H (0.068 ml, 101 mg, 1.049 mmol) was
added dropwise over 2h to a soln. of 29b (145 mg, 0.524 mmol) in CH2Cl2 (10 ml) at 0°C. The
reaction mixture was poured into sat. aq. NaHCO3 (10 ml). The aq. phase was extracted with
Et2O (3 x 10 ml). The org. phase was dried (Na2SO4), concentrated and bulb-to-bulb distilled to
afford a 78:22 mixture of E-/Z-30 in 60% yield. IR: 2965, 2928, 2868, 2828, 1666, 1454, 1381,
1360, 1288, 1202, 1166, 1117, 1057, 986, 803, 764, 615. 1H-NMR: 5.30 (t, J = 6.9, 1H); 3.06 (d,
J = 6.9, 2H); 2.52 (q, J = 7.2, 4H); 2.10-2.03 (m, 4H); 1.90 (t, J = 6.4, 2H); 1.68 (s, 3H); 1.60 (s,
13
3H); 1.59-1.55 (m, 2H); 1.43-1.40 (m, 2H); 1.04 (t, J = 7.2, 6H); 0.99 (s, 6H). C-NMR: 138.7
(s); 137.0 (s); 127.0 (s); 121.2 (d); 50.6 (t); 46.7 (2t); 40.4 (t); 39.9 (t); 35.0 (s); 32.8 (t); 28.6
(2q); 27.5 (t); 19.8 (q); 19.6 (t), 16.4 (q); 11.8 (2q). MS: 277 (9, M+.), 262 (8), 204 (11), 189 (19),
140 (100), 137 (85), 126 (26), 124 (19), 121 (10), 111 (10), 95 (40), 93 (13), 91 (11), 86 (32), 81
(30), 79 (10), 74 (41), 69 (16), 67 (14), 58 (58), 55 (12), 41 (18).
N-Ethyl-N-(((1RS,4aRS,8aRS)-2,5,5,8a-tetramethyl-1,4,4a,5,6,7,8,8a-octahydronaphthalen-1-
yl)methyl)ethanamine 31a. A 60% aq. H2O2 soln. (2.039 g, 1.837 ml, 36.0 mmol) was added
dropwise to a soln. of a 55:45 mixture of 31g/31a (1.996 g, 7.19 mmol) in EtOH (10 ml) at 20°C.
After 1 h at 20°C the EtOH was concentrated at 20°C and replaced by AcOEt (20 ml). 10% Pd/C
(20 mg) was added and the suspension was stirred at 20°C for 4.5 h, until no more gas evolved.
This suspension was filtered over Celite®. The org. phase was washed with brine (Na2SO4),
concentrated and purified by CC/SiO2 (cyclohexane/AcOEt 99:1 to 9:1) to afford pure 31a in
27% yield (60% yield based on pure 31a), besides pure 4.34) Alternatively, CF3SO3H (0.62 ml,
1.05g, 7.0 mmol) was added dropwise to a soln. of 29b (971 mg, 3.5 mmol) in MeNO2 (10 ml) at
34
)
When pure 31g was treated under the same conditions, pure 4 was isolated in 58% yield.
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-20°C. After 2h at -20°C the reaction mixture was poured onto sat. aq. NaHCO3 (10 ml). The aq
phase was extracted with Et2O (3 x 10 ml). The org. phase was washed with H2O (3 x 10 ml),
dried (Na2SO4), then concentrated to afford after bulb-to-bulb distillation a 7:3 mixture of
31a/31g in 81% yield. IR: 2963, 2922, 2865, 2846, 2796, 1455, 1442, 1380, 1365, 1343, 1304,
1
1267, 1212, 1197, 1162, 1133, 1121, 1074, 1056, 1007, 982, 962, 918, 845, 810, 775, 636. H-
NMR: 5.39 (brd, J = 4.2, 1H); 2.61 (ddt, J = 7.2, 14.6, 20.2, 2H); 2.37 (dq, J = 7.0, 13.6, 4H);
2.23 (dd, J = 8.2, 12.7, 1H); 2.02 (dq, J = 3.0, 13.0, 1H); 1.99-1.94 (m, 1H); 1.87-1.84 (m, 1H);
1.77 (s, 3H); 1.53 (dt, J = 3.2, 13.3, 1H); 1.44 (quint, J = 3.5, 1H); 1.43-1.39 (m, 2H); 1.23-1.15
(m, 2H); 0.97 (t, J = 7.0, 6H); 0.88 (s, 3H); 0.86 (s, 3H); 0.75 (s, 3H). 13C-NMR: 136.3 (s); 121.9
(d); 52.8 (t); 51.6 (d); 50.3 (d); 46.0 (2t); 42.2 (t); 39.1 (t); 36.1 (s); 33.3 (q); 33.1 (s); 23.8 (t);
22.4 (q); 22.0 (q); 18.9 (t); 13.7 (q); 11.4 (2q). MS: 277 (0, M+.), 86 (100).
N-Ethyl-N-(((4aRS,8aRS)-2,5,5,8a-tetramethyl-3,4,4a,5,6,7,8,8a-octahydronaphthalen-1-
yl)methyl)ethanamine 31b. CF3SO3H (0.62 ml, 1.05g, 7.0 mmol) was added dropwise to a soln.
of 29b (971 mg, 3.5 mmol) in MeNO2 (10 ml) at 0°C. After 7h at 0°C the reaction mixture was
poured onto sat. aq. NaHCO3 (10 ml). The aq. phase was extracted with Et2O (3 x 10 ml). The
org. phase was washed with H2O (3 x 10 ml), dried (Na2SO4), then concentrated to afford after
bulb-to-bulb distillation 31b in 75% yield. IR: 2963, 2922, 2866, 2843, 2790, 1455, 1381, 1367,
1
1342, 1287, 1194, 1168, 1120, 1067, 1047, 1025, 978, 811, 798, 776. H-NMR: 3.06 (d, J =
13.0, 1H); 2.88 (d, J = 13.0, 1H); 2.55 (dq, J = 7.0, 12.8, 2H); 2.22 (dq, J = 7.0, 12.8, 2H); 2.07-
2.02 (m, 2H); 1.66-1.50 (m, 2H); 1.61 (s, 3H); 1.47-1.37 (m, 3H); 1.17 (ddd, J = 4.0, 13.2, 26.0,
2H); 1.12-1.07 (m, 2H); 1.09 (s, 3H); 0.98 (t, J = 7.0, 6H); 0.87 (s, 3H); 0.85 (s, 3H). 13C-NMR:
138.0 (s); 129.8 (s); 51.4 (d); 51.4 (t); 45.9 (2t); 42.0 (t); 38.3 (s); 37.0 (t); 33.9 (t); 33.5 (q); 33.4
(s); 21.9 (q); 21.0 (q); 20.2 (q); 19.2 (t); 19.1 (t); 11.9 (2q). MS: 277 (45, M+.), 189 (5), 133 (8),
119 (10), 107 (10), 105 (13), 93 (11), 91 (13), 86 (61), 72 (88), 58 (100), 55 (11), 41 (12).
N-Ethyl-N-(((1RS,4aRS,8aRS)-5,5,8a-trimethyl-2-methylenedecahydronaphthalen-1-
yl)methyl)ethanamine 31g. Isolated in 33% yield during the purification of a 26:58:16 mixture of
30/31g/31a (vide supra). IR: 2964, 2930, 2867, 2843, 2795, 1643, 1459, 1442, 1382, 1366, 1201,
1
1167, 1120, 1056, 1056, 993, 977, 963, 883, 774, 668. H-NMR: 4.87 (brq, J = 1.5, 1H); 4.72
(brq, J = 1.5, 1H); 2.58 (dd, J = 7.0, 14.0, 20.0, 2H); 2.52-2.43 (m, 4H); 2.39 (ddd, J = 2.3, 4.2,
12.6, 2H); 2.03 (dt, J = 5.0, 12.8, 1H); 1.88-1.84 (m, 2H); 1.72 (dquint, J = 2.8, 13.0, 1H); 1.56
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(tq, J = 3.5, 13.0, 1H); 1.48 (dquint, J = 3.3, 14.0, 1H); 1.41-1.37 (m, 1H); 1.31 (dq, J = 4.0, 12.8,
1H); 1.20 (dt, J = 4.0, 12.8, 1H); 1.15-1.10 (m, 1H); 0.99 (t, J = 7.0, 6H); 0.88 (s, 3H); 0.81 (s,
13
3H); 0.69 (s, 3H). C-NMR: 148.6 (s); 107.3 (t); 55.7 (d); 54.0 (d); 48.2 (t); 46.9 (2t); 42.1 (t);
39.5 (s); 38.9 (t); 38.4 (t); 33.7 (q); 33.6 (s); 24.3 (t); 21.8 (q); 19.4 (t); 14.8 (q); 10.9 (2q). MS:
277 (1, M+.), 86 (100).
N-Ethyl-N-(((1RS,2SR,4aSR)-2,4a,5,5-tetramethyl-1,2,3,4,4a,5,6,7-octahydronaphthalen-1-
yl)methyl)ethanamine 31r. Conc. H2SO4 (0.274 g, 0.149 ml, 2.80 mmol) was added dropwise to
a soln. of 29b (485 mg, 1.748 mmol) in CH2Cl2 (20 ml) at 0°C. After 18h at 20°C, the reaction
mixture was poured into sat. aq. NaHCO3 (20 ml). The aq. phase was extracted with Et2O (3 x 20
ml). The org. phase was washed with brine, dried (Na2SO4), and concentrated to afford
quantitatively a 26:74 mixture of 31r/31b. Purification by CC/SiO2 (cyclohexane/AcOEt 99:1 to
1:1) afforded pure 31r in 8% yield, as well as pure 31b in 32% yield. IR: 2963, 2923, 2869,
2838, 2797, 1456, 1376, 1350, 1291, 1201, 1176, 1067, 1028, 834, 803, 770, 663. 1H-NMR: 5.32
(t, J = 3.5, 1H); 2.78 (dd, J = 10.9, 12.6, 1H); 2.60 (dq, J = 6.0, 7.0, 2H); 2.41 (dq, J = 6.0, 7.0,
2H); 2.10 (dd, J = 2.8, 12.6, 1H); 2.08-1.98 (m, 3H); 1.91 (dt, J = 5.6, 18.2, 1H); 1.85 (dt, J =
4.0, 13.7, 1H); 1.76-1.69 (m, 2H); 1.28-1.24 (m, 1H); 1.21-1.08 (m, 2H); 1.00 (t, J = 7.0, 6H);
13
0.99 (s, 3H); 0.95 (s, 3H); 0.90 (d, J = 7.4, 3H); 0.83 (s, 3H). C-NMR: 142.1 (s); 123.7 (d);
61.0 (t); 49.4 (d); 47.7 (2t); 39.8 (s); 35.4 (s); 33.4 (t); 29.3 (d); 24.8 (t); 24.5 (q); 23.8 (t); 23.5
(q); 23.3 (q); 23.2 (t); 20.0 (q); 12.1 (2q). MS: 277 (0, M+.), 86 (100).
4-(2-(2,6,6-Trimethylcyclohex-1-en-1-yl)ethyl)-3,6-dihydro-2H-pyran 32. Obtained in 57% yield
according to the procedure used for 11. IR: 2954, 2919, 2850, 1744, 1461, 1377, 1233, 1129,
1029, 971, 851, 720. 1H-NMR: 5.44 (brs, 1H); 4.13 (brd, J = 2.6, 2H); 3.80 (t, J = 5.5, 2H); 2.11-
2.00 (m, 6H); 1.91 (t, J = 6.2, 2H); 1.60 (s, 3H); 1.58-1.55 (m, 2H); 1.43-1.40 (m, 2H); 0.99 (s,
6H). 13C-NMR: 136.9 (s); 136.5 (s); 127.3 (s); 118.9 (d); 65.6 (t); 64.5 (t); 39.8 (t); 35.0 (s); 32.8
(t); 32.0 (t); 29.4 (t); 28.6 (2q); 26.8 (t); 19.8 (q); 19.6 (t). MS: 234 (18, M+.), 137 (100), 123
(12), 121 (10), 95 (59), 93 (10), 91 (11), 81 (38), 79 (11), 69 (12), 67 (11), 55 (10), 41 (19).
(Z)-3-(2-(2,6,6-Trimethylcyclohex-1-en-1-yl)ethyl)pent-3-en-1-ol 33. Obtained in 35% yield
from 32 according to the procedure used for 9. IR: 3322, 2925, 2865, 1455, 1375, 1360, 1204,
1041, 864, 826, 817, 625. 1H-NMR: 5.45 (q, J = 6.9, 1H); 3.67 (dt, J = 6.6, 11.3, 2H); 2.38 (t, J =
6.6, 2H); 2.08-2.01 (m, 4H); 1.90 (t, J = 6.3, 2H); 1.69-1.55 (m, 1H); 1.65 (d, J = 6.3, 3H); 1.60
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(s, 3H); 1.44-1.40 (m, 4H); 0.99 (s, 6H). 13C-NMR: 136.9 (s); 136.8 (s); 127.2 (s); 121.5 (d); 61.0
(t); 39.8 (t); 37.4 (t); 35.0 (s); 33.2 (t); 32.8 (t); 28.6 (2q); 28.1 (t); 19.8 (q); 19.5 (t); 13.4 (q).
MS: 236 (7, M+.), 192 (11), 137 (100), 121 (11), 95 (63), 93 (10), 81 (39), 79 (12), 69 (12), 67
(10), 55 (10), 41 (13).
Ethyl (3E,7E)-4,8,12-trimethyltrideca-3,7,11-trienoate 34b. A 100 ml Keim autoclave (stainless
steel, with glass insert) was charged with EtOH/THF (1:1, 40 ml), amine 29b (500 mg, 1.802
mmol), EtI (281 mg, 1.802 mmol) and Pd(PPh3)4 (31.2 mg, 0.027 mmol) before to be sealed. The
reactor was purged with CO, and pressurized to 30 bar, then heated to 60°C. After 1 h, the
pressure was adjusted to 60 bar and the reaction mixture was stirred for 96h. The cold reactor
was purged with N2, and the mixture was poured onto H2O/Et2O 1:1, then acidified with 10% aq.
HCl. The org phase was washed with H2O, brine, dried (Na2SO4), concentrated and purified by
CC/SiO2 (cyclohexane/AcOEt 99:1 to 9:1) to afford 34b in 31-32% yield as a 76:24 E/Z mixture.
IR: 2965, 2921, 2854, 1737, 1445, 1375, 1314, 1254, 1150, 1108, 1096, 1033, 984, 941, 836,
1
744, 694. H-NMR: (3E, 7E)-isomer 5.33 (t, J = 7.2, 1H); 5.13-5.06 (m, 2H); 4.13 (q, J = 7.2,
2H); 3.04 (d, J = 7.2, 2H); 2.11-1.95 (m, 8H); 1.68 (s, 3H); 1.60 (s, 9H); 1.26 (t, J = 7.2, 3H).
(3Z, 7E)-isomer 5.33 (t, J = 7.2, 1H); 5.13-5.06 (m, 2H); 4.12 (q, J = 7.2, 2H); 3.04 (d, J = 7.2,
13
2H); 2.11-1.95 (m, 8H); 1.75 (s, 3H); 1.64 (s, 9H); 1.26 (t, J = 7.2, 3H). (3E, 7E)-isomer C-
NMR: 172.5 (s); 139.0 (s); 135.2 (s); 131.3 (s); 124.4 (d); 123.9 (d); 115.8 (d); 60.5 (t); 39.7 (t);
39.6 (t); 26.7 (t); 26.4 (t); 25.7 (q); 17.7 (q); 16.4 (q); 16.0 (q); 14.2 (q). MS: 278 (3, M+.), 167
(5), 136 (25), 121 (45), 107 (9), 95 (11), 93 (19), 81 (38), 69 (100), 41 (30), 29 (11).
Methyl
2-((4aRS,8aRS)-2,5,5,8a-tetramethyl-3,4,4a,5,6,7,8,8a-octahydronaphthalen-1-
yl)acetate 36a. Similarly to 34b, a mixture of 31b (250 mg, 0.836 mmol), Pd(PPh3)4 (14.5 mg,
0.013 mmol) and MeI (237 mg, 1.672 mmol) in THF/MeOH (20 ml, 50:50) was heated at 60°C
under 60 bar of CO for 144 h. The cold reaction mixture, containing 45% of a new product, was
poured onto H2O (10 ml), then acidified at 0°C with 10% HCl. The org phase was separated,
washed with H2O. The aq. phase was extracted with Et2O (3 x 5 ml). The org. phase was dried
(Na2SO4), and concentrated. The residual oil was purified by CC/SiO2 (cyclohexane/AcOEt
99:1) to afford 36a in 31% yield. (38% yield of recuperated 31b, the conversion was not better
1
after 10-12 days). Rf = 0.22 (99:1). IR: 2950, 2920, 1730, 860. H-NMR: 3.66 (s, 3H); 3.02 (dd,
J = 17.0, 63.0, 2H); 2.50-1.05 (m, 11H); 1.56 (brs, 3H); 0.93 (s, 3H); 0.89 (s, 3H); 0.83 (s, 3H).
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13C-NMR: 173.4 (s); 133.8 (s); 130.2 (s); 51.6 (q) ; 51.4 (d); 41.5 (t); 38.5 (s); 36.2 (t); 33.6 (t);
33.3 (s); 33.2 (q); 32.9 (t); 21.6 (q); 20.0 (q); 19.7 (q); 18.9 (2t). MS: 264 (28, M+.), 249 (37), 217
(11), 205 (12), 190 (100), 179 (31), 175 (84), 167 (12), 163 (25), 153 (32), 141 (13), 135 (12),
133 (24), 121 (35), 119 (43), 109 (26), 107 (26), 105 (42), 95 (19), 93 (29), 91 (29), 81 (14), 79
(16), 77 (14), 55 (14), 41 (19). Camphoraceous and vaguely woody-like.
Ethyl 2-((4aRS,8aRS)-2,5,5,8a-tetramethyl-3,4,4a,5,6,7,8,8a-octahydronaphthalen-1-yl)acetate
36b. A mixture of 36c (1.61g, 6.5 mmol) in EtOH (30 ml) and H2SO4 (96%, 0.2g) was heated at
reflux for 18h. The cold reaction mixture was concentrated, then partitioned between H2O and
AcOEt. The org phase was washed several times with H2O, then satd aq. NaHCO3. The org.
phase was dried (Na2SO4, concentrated, then purified by CC/SiO2, 99:1 to 97:3
cyclohexane/AcOEt) to afford a 14:24:62 mixture of -:-:-isomers. Pure 36b was obtained by
prep GC for analyses. IR: 2952, 2922, 2854, 1734, 1458, 1376, 1259, 1157, 1024, 885, 860, 800.
1H-NMR: 4.16-4.09 (m, 2H); 3.01 (dd, J = 16.9, 66.3, 2H); 2.50-1.05 (m, 11H); 1.56 (s, 3H); 1.23 (t, J
= 7.0, 3H); 0.93 (s, 3H); 0.83 (s, 3H); 0.88 (s, 3H). 13C-NMR: 173.0 (s); 133.9 (s); 130.2 (s); 60.3 (t);
51.4 (d); 41.5 (t); 38.5 (s); 36.3 (t); 33.6 (q); 33.6 (t); 33.3 (s); 33.1 (t); 21.6 (q); 20.1 (q); 19.7
(q); 18.9 (2t); 14.4 (q). MS: 278 (18, M+.), 263 (23), 217 (10), 205 (14), 193 (19), 190 (100), 175
(84), 167 (22), 163 (29), 149 (10), 147 (14), 135 (10), 133 (20), 121 (29), 119 (35), 109 (23), 107
(24), 105 (37), 95 (16), 93 (26), 91 (24), 81 (13), 79 (16), 77 (11), 69 (18), 55 (15), 41 (18). For
analytical data of the other isomers, see the Supplementary Material.
N-Ethyl-N-((2,6,6-trimethylcyclohex-1-en-1-yl)methyl)ethanamine 39. Obtained in 44% yield
after treatment with 40% aq. H2SO4 at 120°C for 20h according to [76], followed by CC/SiO2
(cyclohexane/AcOEt 9:1 to 8:2) purification of the resulting 60:25:15 mixture of -/-/-
isomers. IR: 2953, 2923, 2853, 2791, 1458, 1379, 1288, 1268, 1197, 1176, 1165, 1119, 1067,
1050, 986, 800, 776, 721. 1H-NMR: 3.0 (s, 2H); 2.37 (q, J = 7.0, 4H); 1.96 (t, J = 6.5, 2H); 1.65
13
(s, 3H); 1.64-1.61 (m, 2H); 1.40-1.38 (m, 2H); 1.09 (s, 6H); 0.99 (t, J = 7.0, 6H). C-NMR:
134.7 (s); 130.7 (s); 51.9 (t); 46.0 (2t); 40.8 (t); 34.3 (s); 33.4 (t); 28.9 (2q); 20.5 (q); 19.3 (t);
12.1 (2q). MS: 209 (28, M+.), 95 (12), 93 (10), 86 (58), 81 (10), 73 (40), 72 (34), 58 (100), 41
(9). For analytical data of both N,N-Diethyl--cyclogeranylamine [13][76], and N,N-Diethyl--
cyclogeranylamine [13][76], see the Supplementary Material. Alternatively, obtained in 8% yield
when 3 was treated with nBuLi/HNEt2 according to the procedure used for 44. The major
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10.1002/hlca.201900097
Helvetica Chimica Acta
28
regioisomer of this latter reaction (80:20 mixture) was N-ethyl-N-((2,3,3-trimethylcyclohex-1-en-
1-yl)methyl)ethanamine isolated in 17% yield after acidic extraction and CC/SiO2
(cyclohexane/AcOEt 9:1 to 8:2, see the Supplementary Material).
Methyl 2-(2,6,6-trimethylcyclohex-1-en-1-yl)acetate 40a. Similarly to 34b, a mixture of 39 (100
mg, 0.478 mmol, 80:20 /), Pd(PPh3)4 (8.28 mg, 0.0072 mmol) and MeI (136 mg, 0.955 mmol)
in THF/MeOH (20 ml, 50:50) was heated at 60°C under 60 bar of CO for 142 h. The cold
reaction mixture, containing 47% of a new product plus 39 (26:14 mixture of /), was poured
onto H2O (10 ml), then acidified at 0°C with 10% HCl. The org phase was separated, washed
with H2O. The aq. phase was extracted with Et2O (3 x 5 ml). The org. phase was dried (Na2SO4),
and concentrated. The residual oil was purified by CC/SiO2 (cyclohexane/AcOEt 99:1) to afford
pure 40a in 25% yield. IR: 2923, 2853, 1746, 1458, 1433, 1376, 1362, 1329, 1295, 1258, 1194,
1154, 1131, 1119, 1046, 1004, 932, 884, 749, 673. 1H-NMR: 3.66 (s, 3H); 3.06 (s, 2H); 1.99 (t, J
13
= 6.5, 2H); 1.59 (brs, 3H); 1.61-1.58 (m, 2H); 1.48-1.41 (m, 2H); 0.96 (s, 6H). C-NMR: 173.4
(s); 131.4 (s); 130.4 (s); 51.6 (q); 39.3 (t); 34.7 (s); 33.6 (t); 32.7 (t); 27.9 (2q); 20.3 (q); 19.4 (t).
MS: 196 (20, M+.), 181 (55), 149 (22), 137 (14), 121 (40), 107 (100), 93 (20), 91 (17), 81 (13),
79 (17), 77 (11), 75 (12), 55 (8), 41 (12).
N-Ethyl-N-((3-methylbicyclo[2.2.1]hept-2-en-2-yl)methyl)ethanamine 41. nBuLi (1.6M/THF,
43.5 ml, 69.6 mmol) was added dropwise during 1h to a soln. of 5 (10.0g, 69.6 mmol) and
Et2NH (9.58g, 131 mmol) in THF (100 ml) at 0°C. After 20 min at 20°C, the reaction mixture
was heated at 50°C for 8h. The cold reaction mixture was poured into H2O (20 ml) at 0°C, then
rendered acidic with 10% aq. HCl. The aq. phase was washed with Et2O (3x20 ml), then
rendered basic by addition of 30% aq. NaOH. This aq. phase was extracted with Et2O (3 x 20 ml)
and this org. phase was dried (Na2SO4), then concentrated in vacuo to afford pure 41 in 52%
yield. Bp. 80°C/0.2 mbar. IR: 2954, 2868, 2792, 1469, 1445, 1380, 1369, 1329, 1287, 1275,
1199, 1177, 1116, 1067, 1051, 1036, 1021, 985, 870, 803, 776. 1H-NMR: 2.94 (s, 2H); 2.83 (brs,
1H); 2.58 (brs, 1H); 2.53 (dq, J = 7.0, 12.8, 2H); 2.40 (dq, J = 7.0, 12.5, 2H); 1.64 (s, 3H); 1.62-
1.60 (m, 2H); 1.33 (dquint, J = 2.0, 7.8, 1H); 1.06-0.98 (m, 3H); 1.01 (t, J = 7.0, 3H). 13C-NMR:
139.8 (s); 137.8 (s); 49.0 (t); 47.9 (d); 47.7 (2t); 46.5 (t); 44.9 (d); 26.5 (t); 25.7 (t), 11.8 (q); 11.6
(2q). MS: 193 (34, M+.), 178 (25), 164 (38), 152 (13), 150 (12), 121 (86), 112 (18), 105 (13), 93
(100), 91 (50), 86 (22), 79 (52), 77 (36), 72 (56), 58 (83), 56 (12).
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10.1002/hlca.201900097
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29
Methyl 2-(3-methylbicyclo[2.2.1]hept-2-en-2-yl)acetate 42. A 100 ml Keim autoclave (stainless
steel, with glass insert) was charged with MeOH/THF (1:1, 40 ml), amine 41 (500 mg, 2.59
mmol), MeI (734 mg, 5.17 mmol) and Pd(PPh3)4 (44.8 mg, 0.039 mmol) before to be sealed. The
reactor was purged with CO, and pressurized to 30 bar, then heated to 60°C. After 1 h, the
pressure was adjusted to 60 bar and the reaction mixture was stirred for 168 h. The cold reactor
was purged with N2, and the mixture was poured onto H2O/Et2O 1:1, then acidified with 10% aq.
HCl. The org phase was washed with H2O, brine, dried (Na2SO4), concentrated and purified by
CC/SiO2 (cyclohexane/AcOEt 99:1 to 9:1) to afford 42 in 22% yield. IR: 2956, 2870, 1733,
1
1715, 1445, 1367, 1276, 1255, 1200, 1158, 1121, 1031, 932, 868, 669. H-NMR: 3.67 (s, 3H);
3.09 (d, J = 15.1, 1H); 2.97 (d, J = 15.1, 1H); 2.76 (brs, 1H); 2.61 (brs, 1H); 1.64 (s, 3H); 1.63-
13
1.60 (m, 2H); 1.40-1.36 (m, 1H); 1.06-1.01 (m, 3H). C-NMR: 172.4 (s); 140.3 (s); 132.1 (s);
51.7 (q); 47.6 (d); 46.8 (t); 45.9 (d); 32.6 (t); 26.2 (t); 25.5 (t), 11.9 (q). MS: 180 (20, M+.), 152
(80), 121 (13), 105 (8), 93 (100), 92 (80), 91 (40), 79 (12), 77 (25).
Acknowledgements
We are indebted to both Drs. V. Rautenstrauch, and C. Margot (Firmenich SA) for fruitful
discussions, and to both Drs. H. Sommer and J.-Y. de Saint Laumer (Firmenich SA) for
SPARTAN B3LYP-6-31G** theoretical calculations [47], as well as to Mr. J.- J. Riedhauser
(Firmenich SA) for allowing us to use his hydroformylation facilities. Mr. O. Barbuzzi is also
particularly acknowledged for technical assistance.
Author Contribution Statement
C. C. conceived and designed the experiments, analyzed the data, and wrote the manuscript. D.
S. and C.-A. R. performed the synthetic work.
References
[1]
C. Margot, M. Schlosser, ´A regio- and stereocontrolled access to 2,4-dienols by amide
/alcoholate-promoted ring-opening of dihydropyrans´ Tetrahedron Lett. 1985, 26, 1035-
1038.
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